MXPA06002828A

MXPA06002828A - Methods of stimulating innate immunity using cationic peptides.

Info

Publication number: MXPA06002828A
Application number: MXPA06002828A
Authority: MX
Inventors: Jon-Paul Steven Powers
Original assignee: Univ British Columbia
Priority date: 2003-09-12
Filing date: 2004-09-10
Publication date: 2006-06-23
Also published as: ZA200602754B; TW200526690A; KR20070033314A; JP2007505048A; IL174099A0; CN1901933A

Abstract

A method of identifying a polynucleotide or pattern of polynucleotides regulated by one or more sepsis or inflammatory inducing agents and inhibited by a peptide is described. A method of identifying a pattern of polynucleotide expression for inhibition of an inflammatory or septic response. The method includes contacting cells with LPS, LTA, CpG DNA and/or intact microbe or microbial components in the presence or absence of a cationic peptide; detecting a pattern of polynucleotide expression for the cells in the presence and absence of the peptide, wherein the pattern in the presence of the peptide represents inhibition of an inflammatory or septic response. Also included are compounds and agents identified by the methods of the invention. In another aspect, the invention provides methods and compounds for enhancing innate immunity in a subject.

Description

EFFECTORS OF INNATA IMMUNITY DETERMINATION Field of the Invention The present invention relates generally to peptides and, specifically, to peptides effective as therapeutic agents and for the discovery of drugs related to pathologies that result from microbial infections and to modulate innate immunity or anti-inflammatory activity. Background of the Invention Infectious diseases are the leading cause of deaths around the world. According to a 1999 World Health Organization study, more than 13 million people die of infectious diseases each year. Infectious diseases are the third leading cause of deaths in North America, accounting for 20% of deaths annually and have increased by 50% since 1980. The success of many medical and surgical treatments also depends on the control of infectious diseases . The discovery and use of antibiotics have been one of the greatest achievements of modern medicine. Without antibiotics, doctors would be unable to perform complex surgeries, chemotherapy or most medical interventions, such as catheterization. The current sales of antibiotics are of the order of 26 billion US dollars around the world. However, the overuse and sometimes unjustified use of antibiotics have resulted in the evolution of new strains of bacteria resistant to antibiotics. Antibiotic resistance has become part of the medical landscape. Bacteria such as vancomycin-resistant Enterococcus, VRE-resistant Staphylococcus aureus and methicillin and MRSA can not be treated with antibiotics, and patients suffering from infections with such bacteria often die. The discovery of antibiotics has proven to be one of the most difficult areas for the development of new drugs and many large pharmaceutical companies have cut or completely stopped their antibiotic development programs. However, with the dramatic increase in antibiotic resistance, including the emergence of non-treatable infections, there is a clear and unmet medical need for novel types of anti-microbial therapies and agents that impact on innate immunity would be one such kinds of agents. The innate immune system is an effective and evolved general defense system. The elements of innate immunity are always present at low levels and are activated very quickly when stimulated. Stimulation may include interaction of bacterial signaling molecules with pattern recognition receptors on the surfaces of body cells or other disease mechanisms. Every day, humans are exposed to tens of thousands of potential pathogenic microorganisms through the food and water they ingest, the air they breathe, and the surfaces, pets and people they touch. The innate immune system acts to prevent these pathogens from causing diseases. The innate immune system differs from the so-called adaptive immunity (which includes antibiotics and B and T lymphocytes specific to antigens) because it is always present, is effective immediately, and is relatively non-specific for any given pathogen. The adaptive immune system requires amplification of specific recognition elements and in this way it takes days to weeks to respond. Even when adaptive immunity is pre-stimulated by vaccination, it may take three or more days to respond to a pathogen, while innate immunity is available immediately or quickly (hours). Innate immunity involves a variety of effector functions including phagocyigotic cells, complement, etc., but is generally incompletely understood. In general terms, many innate immune responses are "triggered" by the ligation of microbial signaling molecules with pattern recognition receptors called Toll-like receptors on the surface of host cells. Many of these effector functions are grouped together in the inflammatory response. Nevertheless, an overly severe inflammatory response can result in responses that are harmful to the body and, in an extreme case, sepsis and potentially death. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the tumor necrosis factor (TNF-) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external component of the bacterial membrane, lipopolysaccharide [LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococcal, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-a. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LIA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Also, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and T cells of memory through interaction with CCR6. Similarly, porcine cationic peptide PR-39 was found to be chemotactic for neutrophils. However, it is not clear if peptides from different structures and compositions share these properties. The only known cathelicidin in humans, LL-37, is produced by myeloid precursors, testes, human keratinocytes during inflammatory disorders and the epithelium of the respiratory tract. The characteristic aspect of the cathelicidin peptides is a high level of sequence identity in the prepro regions of the N-terminus, called the catelin domain. The cathelicidin peptides are stored as precursors of inactive pro-peptides which, when stimulated, are processed into active peptides. SUMMARY OF THE INVENTION The present invention is based on the original and highly influential discovery that based on the expression patterns of polynucleotides regulated by the endotoxic lipopolysaccharide, lipoteichoic acid, CpG DNA, or other cellular components (e.g., microbe or its cellular components), and affected by cationic peptides, novel compounds that block or reduce sepsis and / or inflammation in a subject can be searched by means of analyzes. In addition, based on the use of cationic peptides as a tool, selective enhancers of innate immunity that do not trigger the sepsis reaction and that can block / buffer the inflammatory and / or septic responses can be identified. Thus, in one embodiment, a method of identifying a polynucleotide or polynucleotide pattern regulated by one or more sepsis-inducing or inflammatory agents and inhibited by a cationic peptide is provided. The method of the invention includes contacting the polynucleotide (s) with one or more sepsis or inflammation-inducing agents and contacting the polynucleotide (s) with a cationic peptide., either simultaneously or immediately after it. Differences in expression are detected in the presence and absence of the cationic peptide, and a change in expression, either up or down regulation, is indicative of a polynucleotide or pattern of polynucleotides that are regulated by a sepsis-inducing agent or inflammation and inhibited by a cationic peptide. In another aspect, the invention provides one or more polynucleotides identified by the above method. Examples of sepsis or inflammation regulating agents include LPS, LTA or CpG DNA or microbial components (or any combination thereof), or related agents.

In another embodiment, the invention provides a method of identifying an agent that blocks sepsis or inflammation, including combining a polynucleotide identified by the aforementioned method with an agent, wherein the expression of the polynucleotide in the presence of the agent is modulated in comparison with the expression in the absence of the agent, and where the modulation in the expression affects an inflammatory or septic response. In another embodiment, the invention provides a method of identifying a pattern of polynucleotide expression for inhibition of an inflammatory or septic response by 1) contacting cells with LPS, LTA and / or CpG DNA in the presence or absence of a cationic peptide. , and 2) detecting a polynucleotide expression pattern for the cells in the presence and absence of the peptide. The pattern obtained in the presence of the peptide represents the inhibition of an inflammatory or septic response. In another aspect, the pattern obtained in the presence of the peptide is compared to the pattern of a test compound to identify a compound that provides a similar pattern. In another aspect, the invention provides a compound identified by the above method. In another embodiment, the invention provides a method of identifying an agent that enhances innate immunity by contacting a polynucleotide or polynucleotides encoding a polypeptide involved in innate immunity, with an agent of interest, wherein expression of the polynucleotide in the presence of of the agent is modulated in comparison to the expression of the polynucleotide in the absence of the agent and where the modulated expression results in an improvement in the innate immunity. Preferably, the agent does not stimulate a sepsis reaction in a subject. In one aspect, the agent increases the expression of an anti-inflammatory polynucleotide. Exemplary but non-limiting anti-inflammatory polynucleotides encode proteins such as a homolog 1 of the IL-1 R antagonist (167887), IL-10 R beta (486393), IL-10 R alpha (U006722), member Ib of the TF receptor (AA150416), receptor member 5 of the TNF receptor (H98636), member 11b of the TNF receptor (AA194983), downstream of the IK cytokine of HLA II (R39227), response member 2 to growth early inducible by TGF-B (?? 473938), CD2 (AA927710), IL-19 (NM_ 013371), or IL-10 (M57627). In one aspect, the agent reduces the expression of polynucleotides encoding protease-ina subunits involved in the activation of NF-? such as the proteasome sub-unit 26S (NM_013371). In one aspect, the agent can act as an antagonist of protein kinases. In one aspect, the agent is a peptide selected from SEQ ID NO: 4-54. In another embodiment, the invention provides a method of identifying a pattern of expression of polynucleotides for identification of a compound that selectively enhances innate immunity. The invention includes detecting an expression pattern of polynucleotides for cells contacted in the presence and absence of a cationic peptide, wherein the pattern in the presence of the peptide represents stimulation of the innate immunity; detecting a polynucleotide expression pattern for cells contacted in the presence of a test compound, wherein a standard with the test compound that is similar to the pattern observed in the presence of the cationic peptide is indicative of a compound that enhances innate immunity. It is preferred that the compound does not stimulate a septic reaction in a subject. In another embodiment, the invention provides a method for lowering a state of infection in a mammalian subject from a nucleic acid sample of the subject by identifying in the nucleic acid sample an expression pattern of polynucleotides and emplified by an increase in the expression of polynucleotides of at least 2 polynucleotides in Table 50, 51 or 52, compared to an uninfected subject. Also included is a polynucleotide expression pattern obtained by any of the methods described above. In another aspect, a cationic peptide that is a CXCR-4 antagonist is provided. In yet another aspect, there is provided a method of identifying a cationic peptide that is a CXCR-4 antagonist by contacting T cells with SDF-1 in the presence or absence of a test peptide and measuring chemotaxis. A reduction in chemotaxis in the presence of the test peptide is indicative of a peptide that is a CXCR-4 antagonist. The cationic peptide also acts to reduce the expression of the polynucleotide (NM_013371) of the SDF-1 receptor. In all of the methods described above, the compounds or agents of the invention include, but are not limited to, peptides, cationic peptides, peptide mimetics, chemical compounds, polypeptides, nucleic acid molecules, and the like. In still another aspect of the invention, an isolated cationic peptide is provided. An isolated cationic peptide of the invention is represented in one of the following general formulas and the single letter amino acid code: X: X2X3IX4PX41 ?? 5? 2 ?! (SEQ ID NO: 4), where Xx is one or two of R, L or K, X2 is one of C, S or A, X3 is one of R or P, X4 is one of A or V, and X5 is one of V or W; 1LX2X3KX4 2 5 3PX3X1 (SEQ ID NO: 11), where X1 is one or two of D, E, S, T or N, X2 is one or two of P, G or D, X3 is one of G, A, V , L, I or Y, X4 is one of R, K or H, and X5 is one of S, T, C, M or R; X: X2X3X4 X4WX4X5K (SEQ ID NO: 18), where Xx is one to four selected from A, P or R, X2 is one or two aromatic amino acids (F, Y, and W), X3 is one of P or K, X4 is one, two or none of A, P, Y or W, and X5 is one to three selected from R or P; X1X2X3X4X1VXÍX4RGX4X3X4X1X3X1 (SEQ ID NO: 25), where Xx is one or two of RK, X2 is a polar or charged amino acid (S, T, M, N, Q, D, E, K, R and H), X3 is C , S,, D or A, and X4 is F, I, V, M or R; X1X2X3X4X1VX5X4RGX4X5X4X1X3X1 (SEQ ID NO: 32), where X1 is one or two of R or K, X2 is a polar or charged amino acid (S, T, M, N, Q, D, E, K, R and H), X3 is one of C, S, M, D or A, X4 is one of F, I, V, M or R, and X5 is one of A, I, S, M, D or R; and KX1KX2FX2KMLMX2ALKKX3 (SEQ ID NO: 39), where Xx is a polar amino acid (Cr S, T, M, N and Q), X2 is one of A, L, S, or K, and X3 is from 1 to 17 amino acids selected from G, A, V, L, I, P, F, S, T, K and H; KWKX2X1X1X2X2X1X2X2X1X1X2X2IFHTALKPISS (SEQ ID NO: 46), where x is a hydrophobic amino acid and X2 is a hydrophilic amino acid. Additionally, in another aspect the invention provides isolated cationic peptides KWKSFLRTFKSPVRTVFHTALKPISS (SEQ ID NO: 53) and KWKSYAHTIMSPVRLVFHTALKPISS (SEQ ID NO: 54). Also provided are nucleic acid sequences encoding the cationic peptides of the invention, vectors including such polynucleotides, and host cells containing the vectors. In another embodiment, the invention provides methods for stimulating or enhancing innate immunity in a subject, comprising administering to the subject a peptide of the invention, for example the peptides set forth in SEQ ID NO: 1-4, 11, 18 , 25, 32, 39, 46, 53 or 54. As shown in the Examples herein, innate immunity can be evidenced by activation, proliferation, monocyte differentiation or activation of the MAP kinase pathway alone of example. In one aspect, the method includes administering additionally a serum factor such as GM-CSF to the subject. The subject is preferably any mammal and more particularly a human subject. In another embodiment, the invention provides a method of stimulating innate immunity in a subject who has or is at risk of having an infection, which includes administering to the subject a sub-optimal concentration of an antibiotic in combination with a peptide of the invention. In one aspect, the peptide is that of SEQ ID NO: 1 or SEQ ID NO: 7. Brief Description of the Drawings Figure 1 demonstrates the synergy of SEQ ID NO: 7 with cefepime to cure S. aureus infections . ? CD-1 mice (8 / group) were given 1 x 107 S. aureus in 5% porcine mucin via IP injection. The test compound (50-2.5 mg / kg) was given via IP injection separated 6 hours after the inoculation of S. aureus. At this time, cefepime was also given at a dose of 0.1 mg / kg. The mice were sacrificed 24 hours later, the blood was removed and plated for viable counts. The average ± standard error is displayed. This experiment was repeated twice.

Figure 2 shows that exposure to SEQ ID NO: 1 induces phosphorylation of ER 1/2 and p38. Levigados of monocytes derived from human peripheral blood were exposed to 50 ug / ml of SEQ ID NO: 1 for 15 minutes. A) Specific anti-bodies for the phosphorylated forms of ERK and p38 were used to detect the activation of ERK1 / 2 and p38. All tested donors showed increased phosphorylation of ERK1 / 2 and p38 is response to treatment with SEQ ID NO: 1. A representative donor of eight. Relative amounts of phosphorylation of ERK (B) and p38 © were determined by dividing the intensities of the phosphorylated bands by the intensity of the corresponding control band, as described in the materials and methods section. Figure 3 shows that the phosphorylation of ERK1 / 2 induced by LL-37 occurs in the absence of serum and the magnitude of phosphorylation depends on the type of serum present. The monocytes derived from human blood were treated with 50 μg / l of LL-37 for 15 minutes. The levigates were run on 12% acrylamide gel, then transferred to nitrocellulose membrane and probed with specific anti-bodies for the phosphorylated (active) form of the kinase. To normalize protein loading, the spots were re-probed with β-actin. The quantification was done with the ImageJ software. The interleaved page of Figure 3 demonstrates that LL-37 is unstable to induce MAPK activation in human monocytes under serum-free conditions. The cells were exposed to 50 mg / ml LL-37 (+), or endotoxin-free water (-), as a vehicle control, for 15 minutes. (A) After exposure to LL-37 in medium containing 101% fetal calf serum, ERK1 / 2 was detectable; however, phosphorylation of ERK1 / 2 was not detected in the absence of serum (n = 3). (B) Elk-l, a downstream transcription factor of ERK1 / 2, was activated (phosphorylated), when exposed to 50 μg / ml of LL-37 in medium containing 10% fetal calf serum, but not in the absence of serum (n = 2). Figure 4 shows that activation of ERK1 / 2 induced by LL-37 occurs at lower concentrations and is amplified in the presence of certain cytokines. When freshly isolated monocytes were stimulated in medium containing both GM-CSF (100 ng / ml) and IL-4 (100 ng / ml), the phosphorylation of ERKl / 2 induced by IL-37 was evident in concentrations as low as 5 pg / ml. This synergistic activation of ERK1 / 2 seems to be mainly due to GM-CSF. Figure 5 shows that the peptide affects both the transcription of various cytokine genes and the release of IL-8 in the human bronchial epithelial cell line 16HE4o. The cells were grown to confluence on a semi-permeable membrane and stimulated on the apical surface with 50 μg ml of SEQ ID NO: 1 for four hours. A) Cells treated with SEQ ID NO: 1 produced significantly more IL-8 than controls, as detected by ELISA in supernatant harvested from the apical surface, but not from the basolateral surface. The mean value ± standard deviation of three independent experiments is shown, the asterisk indicates p = 0.002. B) RNA was collected from the previous experiments and RT-PCR was carried out. Several cytokine genes known to be regulated by either ERK1 / 2 or p38 were up-regulated when stimulated with the peptide. The average of two independent experiments is shown. Detailed description of the invention. The present invention provides novel cationic peptides, characterized by a group of generic formulas, which have the ability to modulate (e.g., up-regulate and / or down-regulate) the expression of polynucleotides, thereby regulating the responses of sepsis and inflammatory and / or innate immunity. "Innate immunity", as used herein, refers to the natural ability of an organism to defend against invasions by pathogens, pathogens or microbes, as used herein., may include, but are not limited to bacteria, fungi, parasites and viruses. The innate immunity is contrasted with the acquired / adaptive immunity in which the organism develops a defensive mechanism based substantially on anti-bodies and / or immune lymphocytes, which is characterized by specificity, amplification capacity and auto versus non-auto discrimination. With innate immunity, broad, non-specific immunity is provided and there is no immunological memory of previous exposure. Notable aspects of innate immunity are effectiveness against a wide variety of potential pathogens, independence from prior exposure to a pathogen, and immediate effectiveness (in contrast to the specific immune response that takes days to weeks to stimulate). In addition, innate immunity includes immune responses that affect other diseases, such as cancer, inflammatory diseases, multiple sclerosis, various viral infections, and the like. As used herein, the term "cationic peptide" refers to an amino acid sequence of about 5 to about 50 amino acids in length. In one aspect, the cationic peptide of the invention is from about 10 to about 35 amino acids in length. A peptide is "cationic" if it has enough positively charged amino acids to have a p-value greater than 9.0. Typically, at least two of the amino acid residues of the cationic peptide will be positively charged, for example lysine or arginine. "Positively charged" refers to the side chains of the amino acid residues, which have a net positive charge at a pH of 7.0. Examples of naturally occurring cationic anti-microbial peptides that can be produced recombinantly according to the invention include defensins, cathelicidins, magainins, melittin, and cecropins, bactenecins, indolicidins, polyphemusins, tachyplesins, and their analogues. A variety of organisms make cationic peptides, molecules used as part of a non-specific defense mechanism against microorganisms. When isolated, these peptides are toxic to a wide variety of microorganisms, including bacteria, fungi, and certain enveloped viruses. Although cationic etyptides act against many pathogens, there are notable exceptions and varying degrees of toxicity. However, this patent discloses additional cationic peptides without toxicity to microorganisms but an ability to protect against infections by stimulating innate immunity, and this invention is not limited to cationic peptides with anti-microbial activity. In fact, many peptides useful in the present invention do not have anti-microbial activity. Cationic peptides known in the art include, for example, the human cathelicidin LL-37, and the bovine neutrophil peptide indolicidin and the bovine variant of bactenecin, Bac2A. LL-37 - LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO: 1) Indolicidin - IPLWKWPWWPWRR-NH2 (SEQ ID NO: 2) Bac2A - RLARIVVIRVAR-NH2 (SEQ ID NO: 3) In innate immunity, the immune response does not depend on antigens. The process of innate immunity may include the production of secretory molecules and cellular components, as noted above. In innate immunity, pathogens are recognized by receptors encoded in the germ line. These Toll-like receptors have broad specificity and are capable of recognizing many pathogens. When cationic peptides are present in the immune response, they help in the response of the host to pathogens. This change in the immune response induces the release of chemokines, which promote the recruitment of immune cells to the site of infection. Chemokines, or chemoattractant chemokines, are a subset of immune factors that mediate chemo-tactical phenomena and other pro-inflammatory phenomena (see Schall, 1991, Cytokine 3: 165-183). Chemokines are small molecules of approximately 70-80 residues in length and can generally be divided into two subgroups, a, which have two N-terminal cysteines separated by a single amino acid (CxC) and β, which have two adjacent cysteines in the term N (CC). RANTES, ??? -? Ay MIP-? ß are members of subgroup ß (reviewed by Horuk, R., 1994, Trends Pharmacol.Sci.r 15: 159-165, Murphy, P., 1994, Annu Rev. Immunol., 12: 593-633). The amino terminus of the RANTES chemokines, MCP-1 and MCP-3 has been implicated in the mediation of cell migration and the inflammation induced by these chemokines. This implication is suggested by the observation that the removal of 8 amino terminal residues of MCP-1, 9 terminal amino residues of MCP-3, and 8 terminal amino residues of RANTES, and the addition of a methionine to the amino terminus of RANTES, antagonize chemotaxis, calcium mobilization and / or the release of enzymes stimulated by their native counterparts (Gong et al., 1996 J. Biol. Chem. 271: 10521-10527, Proudfoot et al., 1996 J. Biol. Chem. 271: 2599-2603). Additionally, chemo-tactical activity similar to chemokine has been introduced in MCP-1 via a double mutation of Tyr 28 and Arg 30 to leucine and valine, respectively, indicating that the internal regions of this protein also play a role in regulating chemotactic activity (Beall et al., 1992, J. Biol. Chem. 267: 3455-3459). The monomeric forms of all the chemokines characterized so far share a considerable structural homology, although the quaternary structures of the a and β groups are different. Although the monomeric structures of the ß and chemokines are very similar, the dimeric structures of the two groups are completely different. An additional chemokine, lymphotactin, which has only one N-terminal cysteine has also been identified and may represent an additional (?) Subgroup of chemokines (Yoshida et al., 1995, FEBS Lett., 360: 155-159; and Ketner et al. , 1994, Science 266: 1395-1399). The chemokine receptors belong to the large family of seven transmembrane domain receptors, coupled to G protein (GCRs) (see, reviews by Honuk, R., 1994, Txends Pharmacol, Sci.15: 159-165) and Murphy. , PM, 1994, Annu., Rev. Immunol., 12: 593-633). Studies of competitive ligation and cross-desensitization have shown that chemokine receptors exhibit considerable promiscuity in ligand ligation. Examples demonstrating promiscuity among ß-chemokine receptors include: CC CKR-1, which binds to RANTES and γ-α (Neote et al., 1993, Cell 72: 415-425), CC CKR-4, which binds to RANTES, MIP-la and MCP-1 (Power et al., 1995, J. Biol. Chem. 270: 19495-19500), and CC CKR-5, which is linked to RANTES, MIP-lo; and MIP-? ß (Alkhatib et al., 1996, Science, in the process of printing, and Dragic et al., 1996, Nature 381-667-674). The erythrocytes possess a receptor (known as Duffy antigen) that binds to both a and β chemokines (Horuk et al., 1994, J. Biol. Chem. 269: 17730-17733; Neote et al., 1994, Blood 84: 44-52; and Neote et al., 1993, J. Biol. Chem. 268: 12247-12249). In this way, obvious sequence and structural homologies between chemokines and their receptors allow some overlap in receptor-ligand interactions. In one aspect, the present invention provides the use of compounds including peptides of the invention to reduce sepsis and inflammatory responses by acting directly on host cells. In this regard, there is provided a method of identifying a polynucleotide or polynucleotides that are regulated by one or more sepsis or inflammation-inducing agents, where the regulation is altered by a cationic peptide. Such sepsis or inflammation inducing agents include, but are not limited to, endotoxic lipopolysaccharide (LPS), lipoteichoic acid (LTA) and / or CpG DNA or intact bacteria or other bacterial components. The identification is carried out by contacting the polynucleotide or polynucleotides with the sepsis or inflammation inducing agents and by contacting them additionally with a cationic peptide, either simultaneously or immediately afterwards. Expression of the polynucleotide in the presence and absence of the cationic peptide is observed and a change in expression is indicative of a polynucleotide or polynucleotide pattern that is regulated by a sepsis-inducing or inflammatory agent and inhibited by a cationic peptide. In another aspect, the invention provides a polynucleotide identified by the method. The release of structural components from infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the ex tumor necrosis factor (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-a. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to its natural release during bacterial infections, treatment with antibiotics can also cause the release of bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the external membrane, taken to a self-promoted outlet through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses. Trends in icrobiology 8: 402-410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Likewise, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and memory T cells through interaction with CCR6. Once identified, such polynucleotides will be useful in methods of determining or analyzing compounds that can block sepsis or inflammation by affecting the expression of the polynucleotide. Such an effect on the expression may be up-regulation or down-regulation of the expression.

By identifying compounds that do not trigger the sepsis reaction and that can block or buffer inflammatory or septic responses, the present invention also presents a method of identifying improvements in innate immunity. Additionally, the present invention provides compounds that are used or identified in the above methods. The candidate compounds are obtained from a wide variety of sources, including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including the expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are readily available or are produced. Additionally, libraries and natural or synthetically produced compounds are easily modified by conventional chemical, physical and biochemical means, and many can be used to produce combinatorial libraries. Known pharmacological agents can be subjected to targeted or random chemical modifications, such as acylation, alkylation, esterification, amidation, and the like to produce structural analogues. Candidate agents are also found among biomolecules, including, but not limited to peptides, peptide mimetics, saccharides, fatty acids, steroids, purines, pyrimidines, polypeptides, polynucleotides, chemical compounds, derivatives, structural analogues or combinations thereof. The incubation components of a determination assay or analysis include conditions that allow contact between the test compound and the polynucleotides of interest. The contact includes in solution and in solid phase, or in a cell. The test compound can optionally be a combinatorial library for determination or analysis of a plurality of compounds. The compounds identified in the method of the invention can be further evaluated, detected, cloned, sequenced, and the like, either in solution or after ligation to a solid support, by any method usually applied to the detection of a compound. Generally, in the methods of the invention, a cationic peptide is used to detect and locate a polynucleotide that is essentially in the process of sepsis or inflammation. Once identified, a polynucleotide expression pattern can be obtained by observing the expression in the presence and absence of the cationic peptide. The pattern obtained in the presence of the cationic peptide is then useful to identify additional compounds that can inhibit the expression of the polynucleotide and thereby both block sepsis or inflammation. It is well known to those skilled in the art that non-peptide chemicals and peptide mimetics can mimic the ability of peptides to bind to receptors and enzyme binding sites and thus can be used to block or stimulate biological reactions. Where a compound of further interest provides a polynucleotide expression pattern similar to that of expression in the presence of a cationic peptide, the compound is also useful in the modulation of sepsis or an innate immune response. In this manner, the cationic peptides of the invention, which are known inhibitors of sepsis and inflammation and enhancers of innate immunity, are useful as tools in the identification of additional compounds that inhibit sepsis and inflammation and increase immunity. innate As can be seen in the examples below, the peptides of the invention have a diffused ability to reduce the expression of polynucleotides regulated by LPS. Elevated levels of endotoxin in the blood are responsible for many of the symptoms observed during a serious infection or inflammation, such as fever and an elevated white blood cell count. Endotoxin is a component of the cell wall of gram-negative bacteria and is a potent trigger of the patho-physiology of sepsis. The basic mechanisms of inflammation and sepsis are related. In Example 1, arrays of polynucleotides were used to determine the effect of cationic peptides on the transcriptional response of epithelial cells. Specifically, the effects on more than 14,000 different probes of specific polynucleotides induced by LPS were observed. The tables show the changes observed with cells treated with peptide compared to control cells. The resulting data indicated that the peptides have the ability to reduce the expression of polynucleotides induced by LPS. Example 2, similarly, shows that the peptides of the invention are capable of neutralizing the stimulation of immune cells by gram-positive and gram-negative bacterial products. Additionally, it is observed that certain proinflammatory polynucleotides are down-regulated by cationic peptides, as specified in Table 24, such as TLR1 (AI339155), TLR2 (T57791), TLR5 (N41021), factor 2 associated with the TNF receptor (T55353), factor 3 associated with the TNF receptor (AA504259), superfamily of the TNF receptor, member 12 (W71984), superfamily of the TNF receptor, member 17 (AA 987627), sub-family B of small inducible cytokines , member 6 (AI889554), IL-12R beta 2 (AA977194), receptor 1 of IL-18 (AA482489), while anti-inflammatory polynucleotides are up-regulated by cationic peptides, as observed in Table 25, as the homologue 1 of the antagonist IL-1R (AI167887), IL-10R beta (AA486393), member IB of the TNF receptor (AA150416), member 5 of the TNF receptor (H98636), members 11b of the TNF receptor (AA194983), down regulator of HLA II IK cytokine (R39227), response 2 of early growth inducible anus TGF-B (AI473938), or CD2 (AA927710). The relevance and application of these results are confirmed by an in vivo application to mice. In another aspect, the invention provides a method of identifying an agent that enhances innate immunity. In the method, a polynucleotide or polynucleotides that encode a polypeptide involved in innate immunity is contacted with an agent of interest. The expression of the polynucleotide is determined, both in the presence and absence of the agent. The expression is compared and the specific modulation of the expression was indicative of an improvement in innate immunity.

In another aspect, the agent does not stimulate a septic reaction, as revealed by the lack of up-regulation of the pro-inflammatory cytokine TNF-. In yet another aspect, the agent reduces or blocks the inflammatory or septic response. In yet another aspect, the agent reduces the expression of TNF-α and / or interleukins, including, but not limited to, IL-β, IL-6, IL-12 p40, 11-12 p70, and IL-8. In another aspect, the invention provides methods of direct regulation of polynucleotides by cationic peptides and the use of compounds including cationic peptides to stimulate elements of innate immunity. In this regard, the invention provides a method of identifying a polynucleotide expression pattern for identification of a compound that enhances innate immunity. In the method of the invention, an initial detection of a polynucleotide expression pattern is performed for cells contacted in the presence and absence of a cationic peptide. The pattern resulting from the expression of polynucleotides in the presence of the peptide represents stimulation of the innate immunity. A polynucleotide expression pattern is then detected in the presence of a test compound, where a resulting pattern with the test compound that is similar to the pattern observed in the presence of the cationic peptide is indicative of a compound that enhances innate immunity. In another aspect, the invention provides compounds that are identified in the above methods. In another aspect, the compound of the invention stimulates the expression of chemokines or chemokine receptors. Chemokines or chemokine receptors may include, but are not limited to, CXCR4, CXCR1, CXCR2, CCR2, CCR4, CCR5, CCR6, MIP-1 alpha, MDC, MIP-3 alpha, MCP-1, MCP-2, MCP -3, MCP-4, MCP-5, and RANTES. In still another aspect, the compound is a peptide, peptide mimetic, chemical compound, or nucleic acid molecule. In still another aspect, the expression pattern of polynucleotides includes the expression of proinflammatory polynucleotides. Such pro-inflammatory polynucleotides may include, but are not limited to, the ring finger protein 10 (D87451), the serine / threonine protein kinase MASK (AB040057), the KIAA0912 protein (AB020719), the KIAA0239 protein (D87076) , RAP1, GTPase activating protein 1 (M64788), the binding protein to the death-like receptor FEM-1 (AB 007856), cathepsin S (M90696), the hypothetical protein FLJ20308 (AK000315), the pim-1 oncogene ( M54915), the proteasome type beta subunit (D290U), the KIAA0239 protein (D87076), mucin 5 tracheo-bronchial sub-type B (AJ001403), the ligature protein to the CREBPa cAMP response element, the alpha M integrin (J03925), Rho-associated kinase 2 (NM_004850), PTD017 protein (AL050361), unknown genes (AK01143, AK034348, AL049250, AL16199, AL031983), and any combination thereof. In still another aspect, the pattern of expression of polynucleotides includes the expression of cell surface receptors which may include, but are not limited to, the retinoic acid receptor (X06614), the G protein coupled receptors (Z94155, X81892, U52219, U22491, AF015257, U66579), the cytokine receptor 7 (CC motif) (L31584), the member 17 of the tumor necrosis factor receptor super family (Z29575), the interferon gamma receptor 2 (U05875) , factor 1 similar to cytokine receptor (AF059293), class I cytokine receptor (AF053004), agent 2 similar to coagulation factor II receptor (thrombin) (U92971), leukemia inhibitory factor receptor (NM_002310 ), the interferon gamma receptor 1 (AL050337). In Example 4 it can be seen that the cationic peptides of the invention alter the expression of polynucleotides in macrophages and epithelial cells. The results of this example show that the pro-inflammatory polynucleotides are down-regulated by cationic peptides (Table 24) while the anti-inflammatory polynucleotides are up-regulated by the cationic peptides (Table 25). It is shown later, for example in Tables 1-15, that cationic peptides can neutralize the host response to the signaling molecules of infectious agents as well as modify the transcriptional responses of host cells, mainly down-regulating the pro-inflammatory response and / or by up-regulating the anti-inflammatory response. Example 5 shows that cationic peptides can aid in the response of the host to pathogens by inducing the release of chemokines, which promote the recruitment of immune cells to the site of infection. The results are confirmed by an in vivo application to mice. It is seen from the examples below that the cationic peptides have a substantial influence on the host response to pathogens in that they aid in the regulation of the host immune response by inducing selective pro-inflammatory responses that, for example, promote the recruitment of immune cells to the site of infection but not inducing potentially harmful pro-inflammatory cytokines. Sepsis seems to be caused in part by an overwhelming pro-inflammatory response to infectious agents. Cationic peptides assist the host in a "balanced" response to pathogens by inducing an anti-inflammatory response and suppressing certain potentially harmful pro-inflammatory responses. In Example 7, the activation of selected MAP kinases was examined to study the basic mechanisms behind the effects of the interaction of cationic peptides with cells. Macrophages activate MEK / ERK kinases, in response to bacterial infection. EK is a MAP kinase kinase that when activated phosphorylates the downstream ERK kinase (regulated extra-cellular kinase), which then dimerizes and translocalises to the nucleus, where it activates transcription factors such as Elk-1 to modify the expression of polynucleotides. It has been shown that MEK / ERK kinases affect the replication of Salmonella within macrophages. Signal transduction by MEK kinase and NADPH oxidase may play an important role in the innate defense of the host against intracellular pathogens. Affecting MAP kinases as shown below by means of cationic peptides has an effect on bacterial infection. Cationic peptides can directly affect kinases. Table 21 demonstrates but is not limited to changes in the expression of MAP kinase polynucleotides in response to the peptide. The kinases include MAP kinase kinase 6 (H070920), MAP kinase kinase 5 (W69649), MAP kinase 7 (H39192), MAP kinase 12 (A1936909) and protein kinase 3 activated by MAP kinase (W68281).

In another method, the methods of the invention can be used in combination, to identify an agent with multiple characteristics, ie a peptide with anti-inflammatory / anti-sepsis activity, and the ability to enhance innate immunity, in part by inducing chemokines in vivo In another aspect, the invention provides a method for inferring a state of infection in a mammalian subject from a nucleic acid sample of the subject by identifying in the nucleic acid sample an expression pattern of polynucleotides exemplified by an increase in the expression of polynucleotides of at least 2 polynucleotides in Table 55 compared to an uninfected subject. In another aspect, the invention provides a method for lowering a state of infection in a mammalian subject from a nucleic acid sample of the subject by identifying in the nucleic acid sample a polynucleotide expression pattern exemplified by an expression of polynucleotides of minus 2 polynucleotides in Table 56 or Table 57 compared to an uninfected subject. In one aspect of the invention, the infection status is due to infectious agents or signaling molecules derived therefrom, such as, but not limited to, gram-negative bacteria and gram-positive bacteria, viral, fungal or parasite agents. In still another aspect, the invention provides a pattern of expression of polynucleotides of a subject having a state of infection identified by the above method. Once identified, such polynucleotides will be useful in methods of diagnosing a condition associated with the activity or presence of such infectious agents or signaling molecules. Example 10 below demonstrates this aspect of the invention. Specifically, Table 61 demonstrates that inhibitors of both MEK and NADPH oxidase can limit bacterial replication (infection of macrophages primed with IFN-β by S. typhimurium triggers a MEK kinase). This is an example of how bacterial survival can be impacted by changing the signaling molecules of the host cell. In still another aspect of the invention, there are presented compounds that inhibit stromal derivative factor-1 (SDF-1) induced by T-cell chemotaxis. Compounds that reduce the expression of the SDF-1 receptor are also presented. Such compounds can also act as an antagonist or inhibitor of CXCR-4. In one aspect, the invention provides a cationic peptide that is a CXCR-4 antagonist. In another aspect, the invention provides a method of identifying a cationic peptide that is a CXCR-4 antagonist. The method includes contacting T cells with SDF-1 in the presence or absence of a test peptide and measuring chemotaxis. A reduction in chemotaxis in the presence of the test peptide is then indicative of a peptide that is a CXCR-4 antagonist. Such compounds and methods are useful in therapeutic applications in patients with HIV. These types of compounds and their utility are demonstrated, for example, in Example 11 (see also Tables 62, 63). In that example, it is shown that cationic peptides inhibit cell migration and thus anti-viral activity. In one embodiment, the invention provides an isolated cationic peptide having an amino acid sequence of the general formula (Formula A): x ^ IX ^ ^ PXsX ^ (SEQ ID NO: 4), where X1 is one or two of R, L 0 K, X2 is one of C, S or A, X3 is one of R or P, X4 is one of A or V, and X5 is one of V or W. Examples of the peptides of the invention include, but are not limited to: LLCRIVPVIPWCK (SEQ ID NO: 5), LRCPIAPVI VCKK (SEQ ID NO: 6), KSRIVPAIPVSLL (SEQ ID NO: 7), KKSPIAPAIPWSR (SEQ ID NO: 8), RRARIVPAIPVARR (SEQ ID NO: 9), and LSRIAPAIP AKL (SEQ ID NO: 10). In another embodiment, the invention provides a linear, isolated, cationic peptide having an amino acid sequence of the general formula (Formula B): X1LX2X3KX4X2X5X3PX3X1 (SEQ ID NO: 11), where xl is one or two of D, E , S, T or N, X2 is one or two of P, G or D, X3 is one of G, A, V, L, 1 or Y, X4 is one of R, K or H, and X5 is one of S, T, C, M or R. Examples of the peptides of the invention include, but are not limited to: DLPAKRGSAPGST (SEQ ID NO: 12), SELPGL HPCVPGS (SEQ ID NO: 13), TTLGPVKRDSIPGE (SEQ ID NO: 14), SLPIKHDRLPATS (SEQ ID NO: 15), ELPLKRGRVPVE (SEQ ID NO: 16), and NLPDLKKPRVPATS (SEQ ID NO: 17).

In another embodiment, the invention provides a linear, isolated, cationic peptide having an amino acid sequence of the general formula (Formula C): X ^ X ^ WX ^ ^ K (SEQ ID NO: 18) (this formula includes CP12a and CP12d), where X1 is one to four selected from A, P or R, X2 is one or two aromatic amino acids (F, Y, and W), X3 is one of P or K, X4 is one, two or none of A, P, Y or W, and X5 is one to three selected from R or P. Examples of the peptides of the invention include, but are not limited to, RPRYPWWP WPYRPRK (SEQ ID NO: 19), RRAWWKAWWARRK (SEQ ID NO: 20), RAPY PWA ARPRK (SEQ ID NO: 21), RPAWKYWWP PWPRRK (SEQ ID NO: 22), RAAFKWAWAWWRRK (SEQ ID NO: 23), and RRRWKWAWPRRK (SEQ ID NO: 24). In another embodiment, the invention provides an isolated hexadecameric cationic peptide having an amino acid sequence of the general formula (Formula D): X1X2X3X4X1VX3X4RGX4X3X4X1X3X1 (SEQ ID NO: 25), where Xx is one or two of RK, X is a polar or charged amino acid (S, T, Mr N, Q, D, Er K, R and H), X3 is C, S, M, D or A, and X4 is F, I, V, M or R Examples of the peptides of the invention include, but are not limited to, RRMCIKVCVRGVCRRKCRK (SEQ ID NO: 26), KRSCFKVSMRGVSRRRCK (SEQ ID NO: 27), KKDAI KVDIRGMD RRAR (SEQ ID NO: 28), RKMVKVDVRGIMIRKDRR (SEQ ID NO: 29), KQCVKVAMRG ALRRCK (SEQ ID NO: 30), and RREAIRRVAMRGRDMKRMRR (SEQ ID NO: 31).

In yet another embodiment, the invention provides an isolated hexadecameric cationic peptide having an amino acid sequence of the general formula (Formula E): X1X2X3X4X1VX5X4RGX4X5X4X1X3X1 (SEQ ID NO: 32), where Xx is one or two of R or K, X2 is a polar or charged amino acid (S, T, M, N, Q, D, E, K, R and H), X3 is one of C, S, M, D or A, X4 is one of F , I, V, M or R, and X5 is one of A, I, S, M, D or R. Examples of the peptides of the invention include, but are not limited to: R CVKRVAMRG11RKRCR (SEQ ID NO: 33) , KKQMMKRVDVRGISVKRKR (SEQ ID NO: 34), KESIKV11RGMMVRMKK (SEQ ID NO: 35), RRDCRRVMVRGIDIKAK (SEQ ID NO: 36), KRTAIKKVSRRGMSVKARR (SEQ ID NO: 37), and RHCIRRVSMRGIIMRRCK (SEQ ID NO: 38). In another embodiment, the invention provides a longer, isolated cationic peptide having an amino acid sequence of the general formula (Formula F): (SEQ ID NO: 39), wherein X 1 is a polar amino acid (C, S) , T, M, N and Q), X2 is one of A, L, S, or K, and X3 is from 1 to 17 amino acids selected from G, A, V, L, I, P, F, S, T , K and H. Examples of the peptides of the invention include, but are not limited to KCKLFKKMLMLALKKVLTTGLPALKL K (SEQ ID NO: 40), KSKSFLK LMKALKKVLTTGLPALIS (SEQ ID NO: 41), KTKKFAKMLMMALKKVVSTAKPLAILS (SEQ ID NO: 42), KMKSFAKMLMLALKKVLKVL T LTKAGLPS (SEQ ID NO: 43), KNKAFAKMLMKALKKVTTAAKPLTG (SEQ ID NO: 44), and KQKLFAKMLMSALKKKTLVTTPLAGK (SEQ ID NO: 45). In yet another embodiment, the invention provides a longer, isolated cationic peptide having an amino acid sequence of the general formula (Formula G): KWKX2X1X1X2X2X1X2X2X1X1X2X2IFHTALKPISS (SEQ ID NO: 46), wherein X1 is a hydrophobic amino acid and X2 it is a hydrophilic amino acid. Examples of the peptides of the invention include, but are not limited to: KWKSFLR FKSPVRTIFHTALKPISS (SEQ ID NO: 47), KWKSYAHTI SPVRLIFHTALKPISS (SEQ ID NO: 48), KWKRGAHRFMKFLSTIFHTALKPISS (SEQ ID NO: 49), KWKKWAHSPRKVLTRIFHTALKPISS (SEQ ID NO: 50), KWKSLVMMFKKPARRIFHTALKPISS (SEQ ID NO: 51), and KWKHALMKAHMLWHMIFHTALKPISS (SEQ ID NO: 52). In still another embodiment, the invention provides an isolated cationic peptide, having an amino acid sequence of the formula: KWKSFLRTFKSPVRTVFHTALKPISS (SEQ ID NO: 53), or KWKSYAHTI SPVRLVFHTALKPISS (SEQ ID NO: 54). The term "isolated", as used herein, refers to a peptide that is substantially free of other proteins, lipids, and nucleic acids (e.g., cellular components with which a peptide produced in vivo would naturally be associated). Preferably, the peptide is at least 70, 80, or more preferably 90% pure by weight. The invention also includes analogs, derivatives, conservative variations, and cationic peptide variants of the enumerated polypeptides, with the proviso that the analog, derivative, conservative variation or variant has a detectable activity in which to increase innate immunity or have anti-activity. -inflammatory It is not necessary for the analog, derivative, variation or variant to have an activity identical to the activity of the peptide from which the analog, derivative, conservative or variant variation is derived. A "variant" of cationic peptide is a peptide that is an altered form of a referred cationic peptide. For example, the term "variant" includes a cationic peptide in which at least one amino acid of a reference peptide is substituted in an expression library. The term "reference" peptide means any of the cationic peptides of the invention (e.g., as defined in the formulas above), from which a variant, derivative, analog, or conservative variation is derived. Included within the term "derivative" is a hybrid peptide that includes at least a portion of each of two cationic peptides (e.g., 30-80% of each of two cationic peptides). Also included are peptides in which one or more amino acids are deleted from the sequence of a peptide listed herein, with the proviso that the derivative has activity in which to increase innate immunity or have anti-inflammatory activity. This can lead to the development of a smaller active molecule that may also have utility. For example, terminal amino or carboxy amino acids may be removed that may not be required to enhance the innate immunity or anti-inflammatory activity of a peptide. Similarly, additional derivatives can be produced by adding one or a few (e.g., less than 5) amino acids to a cationic peptide without completely inhibiting the activity of the peptide. In addition, C-terminal derivatives, e.g., C-terminal methyl esters, and N-terminal derivatives can be produced and are encompassed by the invention. The peptides of the invention include any analogue, homologue, mimic, isomer or other derivative of the peptides disclosed in the present invention, so long as the bio-activity remains, as described herein. Also included is the reverse sequence of a peptide encompassed by the general formulas noted above. Additionally, an amino acid of "D" configuration can be substituted by an amino acid of "L" configuration, and vice versa. Alternatively, the peptide can be chemically cyclized or by addition of two or more cistern residues within the sequence and oxidation to form bisulfide bonds. The invention also includes peptides that are conservative variations of those peptides exemplified herein. The term "conservative variation", as used herein, denotes a polypeptide in which at least one amino acid is replaced by another biologically similar residue. Examples of conservative variations include the substitution of a hydrophobic residue, such as isoleucine, valine, leucine, alanine, cistern, glycine, phenylalanine, proline, tryptophan, tyrosine, norleucine, or methionine, or the substitution of a polar residue for another, such as the replacement of arginine by lysine, glutamic acid by aspartic acid, or glutamine by asparagine, and the like. Neutral hydrophilic amino acids that can be substituted by another include asparagine, glutamine, serine and threonine. The term "conservative variation" also encompasses a peptide having a substituted amino acid in place of an unsubstituted parent amino acid. Such substituted amino acids may include amino acids that have been methylated or amidated. Other substitutions will be known to those skilled in the art. In one aspect, the anti-bodies created for a substituted polypeptide will also specifically bind to the unsubstituted polypeptide. The peptides of the invention can be synthesized by means of commonly used methods, such as those that include t-BOC or FMOC protection of alpha-amino groups. Both methods involve stepwise synthesis in which a single amino acid is added at each step, starting at the C-terminus of the peptide (see Colligan et al., Current Protocols in Immunology, Wiley Interscience, 1991, unit 9). The peptides of the invention can also be synthesized by the well known solid phase peptide synthesis methods, such as those described by Merrifield, J. Mi. Chem. Soc. 85: 2149, 1962, and Stewart and Young, Solid Phase Peptides Synthesis, Freeman, San Francisco, 1969, p. 27-62) using a copoly (styrene-non-divinylbenzene) containing 0.1-1.0 mMol amines / g of polymer. Upon completion of the chemical synthesis, the peptides can be deprotected and cut from the polymer by treatment with liquid HF-10% anisol for about 1/4 to 1 hours at 0 ° C. After the evaporation of the reagents, the peptides are extracted from the polymer with a 1% acetic acid solution, which is then lyophilized to yield the raw material. The peptides can be purified by techniques such as gel filtration on Sephadex G-15 using 5% acetic acid as solvent. The lyophilization of the appropriate fractions of the column levigado renders homogeneous peptide, which can then be characterized by standard techniques such as amino acid analysis, thin layer chromatography, high performance liquid chromatography, ultraviolet absorption spectroscopy, molar rotation, or Measure the solubility. If desired, the peptides can be quantified by Edman degradation in solid phase. The invention also includes isolated nucleic acids (e.g., DNA, cDNA, or RNA) that encode the peptides of the invention. Nucleic acids encoding analogues, mutants, conservative variations, and variants of the peptides described herein are included. The term "isolated", as used herein, refers to a nucleic acid that is substantially free of proteins, lipids and other nucleic acids with which nucleic acids produced in vivo are naturally associated. Preferably, the nucleic acid is at least 70, 80 or preferably 90% pure by weight, and conventional methods can be used to synthesize nucleic acids in vitro instead of in vivo methods. As used herein, "nucleic acid" refers to a polymer of deoxyribonucleotides or ribonucleotides, in the form of a separate fragment or as a component of a larger genetic construct (e.g., operatively linking a promoter to the nucleic acid encoding a peptide of the invention). Numerous genetic constructs (e.g., plasmids and other expression vectors) are known in the art and can be used to produce the peptides of the invention in cell-free systems or prokaryotic or eukaryotic cells (e.g., yeast, insect or mammal). Taking into account the degeneracy of the genetic code, a person skilled in the art can easily synthesize nucleic acids encoding the polypeptides of the invention. The nucleic acids of the invention can be readily used in conventional methods of molecular biology to produce the peptides of the invention. DNA encoding the cationic peptides of the invention can be inserted into an "expression vector". The term "expression vector" refers to a genetic construct such as a plasmid, virus or other vehicle known in the art that can be made by genetic inference to contain a nucleic acid encoding a polypeptide of the invention. Such expression vectors are preferably plasmids containing a promoter sequence that facilitates the transcription of the genetic sequence inserted into a host cell. The expression vector typically contains an origin of replication, and a promoter, as well as polynucleotides that allow phenotypic selection of transformed cells (e.g., a polynucleotide of antibiotic resistance). Various promoters, including inducible and constitutive promoters, can be used in the invention. Typically, the expression vector contains a replicon site and control sequences that are derived from a species compatible with the host cell. Transformation or transfection of a receptor with a nucleic acid of the invention can be carried out using conventional techniques well known to those skilled in the art. For example, where the host cell is E. coli, competent cells capable of DNA acquisition can be prepared using methods known in the art with CaCl 2, MgCl 2 or RbCl. Alternatively, physical means, such as electroporation or micro-injection, may be used. Electroporation allows the transfer of a nucleic acid to a cell by a high-voltage electrical impulse. Additionally, nucleic acids can be introduced into host cells by protoplast fusion, using methods well known in the art. Suitable methods for transforming eukaryotic cells, such as electroporation and lipofection, are also known. "Host cells" or "recipient cells" encompassed by the invention are any cells in which the nucleic acids of the invention can be used to express the polypeptides of the invention. The term also includes any progeny of a host or host cell. Preferred recipient or host cells of the invention include E. coli, S. aureus and P. aeruginosa, although other cells and other gram-negative and gram-positive bacterial organisms, fungi and mammals known in the art may be used, as long as the vectors of expression contain an origin of replication to allow expression in the host. The sequence of cationic peptide polynucleotides used according to the method of the invention can be isolated from an organism or synthesized in a laboratory. Specific DNA sequences encoding the cationic peptide of interest can be obtained by means of: 1) isolation of a double helix DNA sequence from genomic DNA; 2) chemical processing of a DNA sequence to provide the necessary codons for the cationic peptide of interest; and 3) in vitro synthesis of a double helix DNA sequence by reverse transcription of mRNA isolated from a donor cell. In the latter case, a double helix DNA is eventually formed complementing the mRNA, which is generally referred to as cDNA. The synthesis of DNA sequences is frequently the method chosen when the entire amino acid residue sequence of the desired peptide product is known. In the present invention, the synthesis of a DNA sequence has the advantage of allowing the incorporation of codons that are more easily recognized by a bacterial host, thereby allowing high level expression without translation difficulties. In addition, virtually any peptide can be synthesized, including those encoding natural cationic peptides, variants thereof, or synthetic peptides. When the entire sequence of the desired peptide is not known, the synthesis of DNA sequences is not possible and the method chosen is the formation of cDNA sequences. Among standard procedures for isolating cDNA sequences of interest is the formation of a plasmid or phage containing cDNA libraries that are derived from reverse transcription of mRNA, which is abundant in donor cells that have a high level of gene expression. When used in combination with polymerase chain reaction technology, even rare expression products can be cloned. In those cases where significant portions of the amino acid sequence of the cationic peptide are known, the production of single-stranded or double-stranded DNA or RNA probe sequences that duplicate a putatively present sequence in the target cDNA can be used in DNA / DNA hybridization procedures which are carried out on cloned copies of the cDNA, which have been denatured in a single filament form (Jay et al, Nuc Acid Res., 11: 2325, 1983). The peptide of the invention can be administered parenterally or by injection or by gradual infusion over time. Preferably, the peptide is administered in a therapeutically effective amount to enhance or stimulate an innate immune response. Innate immunity has been described herein, although examples of indicators of innate immunity stimulation include, but are not limited to monocyte activation, proliferation, differentiation or activation of the MAP kinase pathway. The peptide can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intra-cavity, or transdermally. Preferred methods for delivery of the peptide include orally, by encapsulation in microspheres or proteinoids, by delivery to the lungs by means of aerosol, or transdermally by iontophoresis or transdermal electroporation. Other methods of administration will be known to those skilled in the art. Preparations for parenteral administration of a peptide of the invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, solutions, emulsions or alcoholic / aqueous suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as, for example, antimicrobial agents, anti-oxidants, chelants, and inert gases and the like. In one embodiment, the invention provides a method for synergistic therapy. For example, peptides such as those described herein may be used in synergistic combination with sub-inhibitory concentrations of antibiotics. Examples of particular classes of antibiotics useful for synergistic therapy with the peptides of the invention include aminoglycosides (e.g., tobramycin), penicillins (e.g., piperacillin), cephalosporins (e.g., ceftazidime), fluoroquinolones (e.g., ciprofloxacin), carbapenem (e.g., imipenem), tetracyclines and macrolides (e.g., erythromycin and clarithromycin). In addition to the antibiotics listed above, typical antibiotics include aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, tobramycin, streptomycin, azithromycin, clarithromycin, erythromycin, stolate / ethylsuccinate / gluceptorate / lactobionate / erythromycin stearate), beta-lactams such as penicillins (e.g., penicillin G, penicillin V, methicillin, nafcillin, oxacilir.a, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin, and piperacillin), or cephalosporins (e.g. cephalothine, cefazolin, cefaclor, cephamandola, cefoxitin, cefuroxime, cefomyxide, cefmetazole, cefotetan, cefprozil, loracarbef, cefetamet, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceflazidime, cefepime, cefixime, cefpodoxime, and cefsulodine). Other classes of antibiotics include carbapenem (e.g., imipenem), monobactams (e.g., aztreonama), quinolones (e.g., fleroxacin, lidixic acid, norfloxacin, ciprofloxacin, ofloxacin, emoxacin, lomefloxacin and cinoxacin), tetracyclines (e.g., doxycycline, minocycline, tetracycline), and glycopeptides (e.g., vancomycin, teicoplanin), for example. Other antibiotics include chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin, mupirocin, and cationic peptides. The effectiveness of the peptides was evaluated therapeutically alone and in combination with sub-optimal concentrations of antibiotics in infection models. S. aureus is a major gram-positive pathogen and a leading cause of antibiotic-resistant infections. Briefly, peptides were tested for their therapeutic efficacy in the S. a reus infection model by injecting them alone and in combination with sub-optimal doses of antibiotics 6 hours after the onset of infection. This would stimulate the circumstances of resistance to antibiotics that develop during an infection, such that the MIC value of the resistant bacteria was too high to allow successful therapy (i.e., the dose of antibiotics applied was sub-optimal). It was shown that the combination of the antibiotic and the peptide resulted in improved efficacy and suggests the potential for combination therapy (see Example 12). The invention will now be described in greater detail by reference to the following non-limiting examples. Although the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of what is described and claimed. EXAMPLE 1 Anti-Seis / Anti-Inflammatory Activity Polynucleotide arrays were used to determine the effect of cationic peptides on the transcriptional response of epithelial cells. The human epithelial cell line A549 was maintained in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS, Medicorp).

A549 cells were plated in 100 mm tissue culture dishes at 2.5 x 10 6 cells / dish, cultured overnight and then incubated with 100 ng / ml E. coli 0111: B4 LPS (Sigma), without (control) or with 50 ug / ml of peptide or medium only for 4 hours. After stimulation, the cells were washed once with buffered saline (PBS) with phosphate, treated with diethyl pyrocarbonate, and separated from the dish using a cell scraper. Total RNA was isolated using RNAqueous (Ambion, from Austin, Texas, United States). The RNA beads were resuspended in RNase-free water containing Superase-In (RNAse inhibitor, Ambion). DNA contamination was removed with the DNA-free kit from Ambion. RNA quality was determined by gel electrophoresis on a 1% agarose gel. The arrays of polynucleotides used were arrays of human operons (the identification number for the genome is PRHU04-S1), which consist of about 14,000 human oligos in duplicate. Probes were prepared from 10 ug of total RNA and marbed with dUTP marbed with Cy3 or Cy5. The probes were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Perkin Elmer array scanner. The image processing software (Imapolynucleo-tide 5.0, Marina Del Rey, California, United States) determines the average intensity of spots, average intensities, and background intensities. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS. In Table 1, the peptide, SEQ ID NO: 27, is shown to potently reduce the expression of many of the polynucleotides up-regulated by E. coli 0111: B4 LPS, as studied by micro-arrays of polynucleotides. Peptide (50 pg / ml) and LPS (0.1 ug / ml) or LPS were only incubated with A549 cells for 4 hours and the RNA was isolated. Five total RNAs were used to make marseted Cy3 / Cy5 cDNA probes and hybridized in human operon arrays (PRHU04). The intensity of the unstimulated cells is shown in the third column of Table 1. The column "ratio: LPS / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS divided by the intensity of the unstimulated cells. The column "Relationship: LPS + ID 27 / control "refers to the intensity of expression of polynucleotides in cells stimulated with LPS and peptide divided between unstimulated cells Table 1: Reduction, by peptide SEQ ID NO: 27, of expression of epithelial cell polynucleotides A549 regulated upwards by E. coll OHl: B4 LPS Number of Function Control: Relationship: Ratio: Access3 of the Gene Immensity LPS / conLPS + ID of Poly- Solo of trol 27 / control nucleotide Medium AL031983 0.032 302.8 5.1 L04510 0.655 213.6 1.4 D87451 3.896 183.7 2.1 AK000869 0.138 120.1 2.3 U78166 0.051 91.7 0.2 AJ001403 0.203 53.4 15.9 AB040057 0.95 44.3 15.8 Z99756 0.141 35.9 14.0 L42243 0.163 27.6 5.2 NM_016216 6.151 22.3 10.9 AK0001589 0.646 19.2 1.3 AL137376 1,881 17.3 0.6 AB007856 2.627 15.7 0.6 AB007854 0.845 14.8 2.2 AK000353 0.453 13.5 1.0 D14539 2.033 11.6 3.1 X76785 0.728 11.6 1.9 M54915 1,404 11.4 0.6 NM_006092 0.369 11.0 0.5 J03925 0.272 9.9 4.2 NM_001663 0.439 9.7 1.7 M23379 0.567 9.3 2.8 K02581 3.099 8.6 3.5 U94831 3.265 7.1 1.5 X70394 1.463 6.9 1.7 AL137614 0.705 6.8 1.0 U43083 0.841 6.6 1.6 AL137648 1.276 6.5 0.8 AF085692 3.175 6.5 2.4 AK001239 2.204 6.4 1.3 NM_001679 2.402 6.3 0.9 L24804 3.403 6.1 1.1 U15932 0.854 6.1 2.1 M36067 1.354 6.1 2.2 AL161951 0.728 5.8 1.9 M59820 0.38 5.7 2.0 AL0500290 2.724 5.6 1.4 NM_002291 1.278 5.6 1.8 X06614 1.924 5.5 0.8 AB007896 0.94 5.3 1.8 AL050333 1.272 5.3 0.6 A 001093 1.729 5.3 2.0 NM_016 06 1.314 5.2 1.2 M86546 1.113 5.2 2.2 X56777 1.414 5.0 1.4 NM_013400 1,241 4.9 2.0 NMJ302309 1.286 4.8 1.9 NM_001940 2.034 4.7 1.2 U91316 2.043 4.7 1.4 X76104 1.118 4.6 1.8 AF131838 1.879 4.6 1.4 AL050348 8.502 4.4 1.7 D42085 1.323 4.4 1.2 X92896 1.675 4.3 1.5 U26648 1.59 4.3 1.4 X85750 1.01 4.3 1.1 D14043 1,683 4.2 1.0 J04513 1.281 4.0 0.9 U19796 1.618 4.0 0.6 AK000087 1.459 3.9 1.0 AK001569 1.508 3.9 1.2 AF189009 1.448 3.8 1.3 Ü60205 1.569 3.7 0.8 AK000562 1.166 3.7 0.6 AL096739 3.66 3.7 0.5 AK000366 15.192 3.5 1.0 NM_006325 1.242 3.5 1.4 X51688 1.772 3.3 1.0 U34252 1,264 3.3 1.2 NM_013241 1,264 3.3 0.6 AF112219 1.839 3.3 1.1 NM_016237 2.71 3.2 0.9 AB014569 2.762 3.2 0.2 AF151047 3.062 3.1 1.0 X92972 2.615 3.1 1.1 AF35309 5.628 3.1 1.3 U52960 1.391 3.1 0.8 J04058 3.265 3.1 1.2 M57230 0.793 3.1 1.0 U78027 3.519 3.1 1.1 AK000264 2.533 3.0 0.6 X80692 2.463 2.9 1.3 L25931 2.186 2.7 0.7 X13334 0.393 2.5 1.1 M32315 0.639 2.4 0.4 NM_004862 6.077 2.3 1.1 AL050337 2.064 2.1 1.0 * All access numbers in Tables 1 through 65 refer to accesses in the GenBank. In Table 2, it is shown that cationic peptides at a concentration of 50 g / ml potently reduce the expression of many of the polynucleotides up-regulated by 100 ng / ml of E. coli 0111: B4 LPS, as studied by micro-arrays of polynucleotides. Peptide and LPS or LPS were only incubated with A549 cells for 4 hours and the RNA was isolated. 5 ug of total RNA was used to make marseted Cy3 / Cy5 cDNA probes and hybridized in arrays of human operons (PRHU04). The intensity of the unstimulated cells is shown in the third column of Table 2. The column "Ratio: LPS / control" refers to the intensity of the expression of polynucleotides in cells stimulated by LPS, divided by the intensity of the cells not stimulated. The other columns refer to the intensity of the expression of polynucleotides in cells stimulated with 1PS and peptide, divided between unstimulated cells. Table 2: Expression of polynucleotides in human A549 epithelial cells, up-regulated by E. col! 0111: B4 LPS, and reduced by cationic peptides Gen Control Number: RelaRelaRelaRelaAcceso Intensity: tion: tion: tion: Only LPS / conLPS + ID LPS + ID LPS + Troll ID 27 / con16 / con- 22 / con Trolley trol trol AL031983 0.03 302.8 5.05 6.91 0.31 L04510 0.66 213.6 1.4 2.44 3.79 D87451 3.90 183.7 2.1 3: 68 4.28 AK000869 0.14 120.1 2.34 2.57 2.58 U78166 0.05 91.7 0.20 16.88 21.37 X03066 0.06 36.5 4.90 12.13 0.98 AK001904 0.03 32.8 5.93 0.37 0.37 AB037722 0.03 21.4 0.30 0.30 2.36 AK001589 0.65 19.2 1.26 0.02 0.43 AL137376 1.88 17.3 0.64 1.30 1.35 L19185 0.06 16.3 0.18 2.15 0.18 J05068 0.04 15.9 1.78 4.34 0.83 AB007856 2.63 15.7 0.62 3.38 0.96 AK000353 0.45 13.5 1.02 1.73 2.33 X16940 0.21 11.8 3.24 0.05 2.26 54915 1.40 11.4 0.63 1.25 1.83 AL122111 0.37 10.9 0.21 1.35 0.03 95678 0.22 7.2 2.38 0.05 1.33 AK001239 2.20 6.4 1.27 1.89 2.25 AC004849 0.14 6.3 0.07 2.70 0.07 X06614 1.92 5.5 0.77 1.43 1.03 AB007896 0.94 5.3 1.82 2.15 2.41 AB010894 0.69 5.0 1.38 1.03 1.80 U52522 1.98 2.9 1.35 0.48 1.38 AK001440 1.02 2.7 0.43 1.20 0.01 NM_001148 0.26 2.5 0.82 0.04 0.66 X07173 0.33 2.2 0.44 0.03 0.51 AF095687 0.39 2.1 0.48 0.03 0.98 NM_016382 0.27 2.1 0.81 0.59 0.04 AB023198 0.39 2.0 0.43 0.81 0.92 Example 2 Neutralization of Immune Cell Stimulation The ability of the compounds to neutralize the stimulation of immune cells by both gram-negative and gram-positive bacterial products was tested. Bacterial products stimulate cells of the immune system to produce inflammatory cytokines and, when this situation is not addressed, can lead to sepsis. Initial experiments used the murine macrophage cell line RAW 264.7, which was obtained from the American Type Culture Collection (Manassas, Virginia, United States), the human epithelial cell line A549, and primary macrophages derived from the bone marrow of BALB mice. c (Charles River Laboratories, of Wilmington, Massachusetts, United States). Mouse bone marrow cells were grown in 150 mm dishes in Dulbecco's modified Eagle's medium (DMEM, Life Technologies, Burlington, Ontario, Canada), supplemented with 20% FBS (Sigma Chemical Co., St. Louis, Missouri, United States) and 20% of conditioned medium with L cells as a source of M-CSF. Once the macrophages were 60-80% confluent, they were deprived of conditioned medium with L cells for 14-16 hours to make the cells quiescent and then subjected to treatments with 100 ng / ml LPS or 100 ng / ml LPS + 20 ug / ml of peptide for 24 hours. The release of cytokines to the culture supernatant was determined by ELISA (R &D Systems, Minneapolis, Minnesota, United States). Cell lines RA 264.7 and A5 9 were maintained in DMEM supplemented with 10% fetal calf serum. RAW 264.7 cells were seeded in 24-well plates at a density of 106 cells per well in DMEM and A549 cells were seeded in 24-well plates at a density of 105 cells per well in DMEM and both were incubated at 37 ° C. in 5% C02 overnight. DMEM was aspirated from cultured cells overnight and replaced with fresh medium. In some experiments, blood was collected from volunteer human donors (according to procedures accepted by the Clinical Research Ethics Board of the University of British Columbra, certified C00-0537) by vein puncture in tubes (Becton Dickinson, Franklin Lakes, New Jersey, United States), containing 14.3 USP units of heparin / ml of blood. The blood was mixed with LPS with or without peptide in polypropylene tubes at 37 ° C for 6 hours. The samples were centrifuged for 5 minutes at 2,000 x g, the plasma was collected and then stored at -20 ° C until it was analyzed in relation to IL-8 by ELISA (R &D Systems). In cell experiments, LPS or other bacterial products were incubated with the cells for 6-24 hours at 37 ° C in 5% CC2. S. typhimurium LPS and E. coli 0111: 334 LPS were purchased from Sigma. Lipoteichoic acid (LTA) of 5. aureus (Sigma) was re-suspended in endotoxin-free water (Sigma). The iimulus amoebocyte lysate assay (Sigma) was carried out in LTA preparations to confirm that the batches were not significantly contaminated by endotoxin. Endotoxin contamination was less than 1 ng / ml, a concentration that did not cause significant cytokine production in RAW 264.7 cells. The unfinished lipoarabinomanana (AraLAM) was a gift from Dr. John T. Belisle of Colorado State University. Mycobacterium AraLAM was filter sterilized and endotoxin contamination was found to be 3.75 ng per 1.0 mg of LAM, determined by the assay of Limulus amoebocyte. At the same time as the addition of LPS (or after, where specifically described), cationic peptides were added in a range of concentrations. The supernatants were removed and tested for cytokine production by ELISA (R & amp; amp; amp;; D Systems). All assays were carried out at least three times with similar results. To confirm the anti-sepsis activity in vivo, sepsis was induced by intra-peritoneal injection of 2 or 3] iq of E. coli 0111: B4 LPS in phosphate buffered saline (PBS, pH 7.2) in CD mice -1 or BALB / c from 8 to 10 weeks old, females, sensitized with galactosamine. In experiments involving peptides, 200 ug was injected into 100 μ? of sterile water in separate intraperitoneal sites within 10 minutes of the LPS injection. In other experiments, CD-1 mice were injected with 400 μg of E. coli 0111: B4 LPS and 10 minutes later peptide (200 μg) was introduced by intra-peritoneal injection. Survival was monitored for 14 hours post-injection. The hyper-production of TNF-a has been classically linked to the development of sepsis. The three types of LPS, LTA or AraLAM used in this example represented products released by both gram-negative and gram-positive bacteria. The peptide, SEQ ID NO: 1, was able to significantly reduce the production of TNF-a stimulated by S. typiimurium, B. cepacía, and E. coli 0111: B4 LPs, the first of these being affected to a somewhat lesser degree (Table 3). At concentrations as low as 1 g / ml of peptide (0.25 nM), a substantial reduction in the production of TNF-a was observed in the last two cases. A different peptide, SEQ ID NO: 3, did not reduce the production of TNF-a induced by LPS in RAW macrophage cells, demonstrating that this is not a uniform and predictable property of the cationic peptides. Representative peptides of each formula were also tested for their ability to affect the production of TNF-a stimulated by E. coli 0111: B4 LPS (Table 4). The peptides had a varied ability to reduce the production of TNF-a although many of them reduced TNF-a by at least 60%. ? certain concentrations, the peptides SEQ ID NO: 1 and SEQ ID NO: 2 may also reduce the ability of the bacterial products to stimulate the production of IL-8 by an epithelial cell line. It is known that LPS is a potent stimulator of the production of IL-8 by epithelial cells. Peptides, at low concentrations (1-20 pg / ml), neutralize the IL-8 induction responses of epithelial cells to LPS (Tables 5-7). The peptide SEQ ID NO: 2 also inhibited the production of IL-8 induced by. LPS in whole human blood (Table 4). Conversely, high concentrations of the peptide SEQ ID NO: 1 (50 to 100 g / ml) actually resulted in increased levels of IL-8 (Table 5). This suggests that the peptides have different effects at different concentrations. The effect of the peptides on inflammatory stimuli was also demonstrated in murine primary cells, in that the peptide SEQ ID NO: 1 significantly reduced the production of TNF-a (> 90%) by macrophages derived from bone marrow of BALB / c mice that had been stimulated with 100 ng / ml of E. coli 0111: B4 LPS (Table 8). These experiments were carried out in the presence of serum, which contains the LPS binding protein (LBP), a protein that can mediate the rapid ligation of 1PS to CD14. The delayed addition of the peptide SEQ ID NO: the supernatants of macrophages one hour after stimulation with 100 ng / ml of LPS from E. coli still resulted in a substantial reduction (70%) in the production of TNF-a (Table 9). Consistent with the ability of SEQ ID NO: 1 to prevent the production of TNF-a induced by LPS in vitro, certain peptides also protected mice against lethal shock induced by high concentrations of LPS. In some experiments, CD-1 mice were sensitized to LPS with a previous injection of galactosamine. The mice sensitized with galactosamine that were injected by 3 μg of E. coli 0111: B4 LPS were all killed within 4-6 hours. When 200 μg of the peptide SEQ ID NO: 1 was injected 15 minutes after LPS, 50% of the mice survived (Table 10). In other experiments, when a higher concentration of LPS was injected into BALB / c mice without D-galactosamine, the peptide protected 100% compared to the control group in which there was no survival (Table 13). Other selected peptides were also found to be protective in these models (Tables 11, 12). The cationic peptides were also able to reduce the stimulation of macrophages by gram-positive bacterial products, such as unfinished lipoarabinomanana of Mycobacterium (AraLA) and LTA of S. aureus. For example, the peptide SEQ ID NO: 1 inhibited the induction of TNF-cx in RAW 264.7 cells by the gram-positive bacterial products, LTA (Table 14), and to a lesser extent AraLAM (Table 15). Another peptide, SEQ ID NO: 2, was also found to reduce the production of TNF-α induced by LTA by RAW 264.7 cells. At a concentration of 1 μg ml, the peptide SEQ ID NO: 1 was able to reduce substantially (>75%) the induction of TNF- production by 1 pg / ml LTA of S. aureus. At 20 g / ml of the peptide SEQ ID NO: 1, there was > 60% inhibition of TNF-a induced by AraLAM. Polymyxin B (PMB) was included as a control to demonstrate that the contaminating endotoxin was not a significant factor in the inhibition by the peptide SEQ ID NO: 1 of TNF-a induced by AraLAM. These results demonstrate that cationic peptides can reduce the response of pro-inflammatory cytokines of the immune system to bacterial products.

Table 3: Reduction by SEQ ID NO: 1 of TNF-a production induced by LPS in RAW 264.7 cells Mouse macrophage cells RAW 264.7 were stimulated with 100 ng / ml of S. typhimurium LPS, 100 ng / ml of LPS of B. cepacia and 100 ng / ml of E. coli 0111: B4 LPS in the presence of the indicated concentrations of the peptide SEQ ID NO: 1 for 6 hours. The concentrations of TNF-α released to the culture supernatants were determined by ELISA. 100% represents the amount of TNF-a that results from RAW 264.7 cells incubated with LPS for only 6 hours (S. typhimurium LPS = 34.5 ± 3.2 ng / ml, B. cepacia LPS = 11.6 + 2.9 ng / ml, and E. coli 0111: B4 LPS = 30.8 ± 2.4 ng / ml). Background levels of TNF-a production by RAW 264.7 cells cultured unstimulated for 6 hours resulted in TNF-a levels ranging from 0.037 to 0.192 ng / ml. The data is from duplicate samples and presented as the average of three experiments plus the standard error. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the tumor necrosis factor (TNF-OI) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-a. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, R.E.W., and R. Lehrer, 1998. Cationic peptides: a ne source of antibiotics. Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria,. They interact with 1PS to permeabilize the outer membrane, taken to a self-promoted outlet through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Likewise, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking oí-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and memory T cells through interaction with CCR6.

Amount of Inhibition of TNF-a (%) * SEQ ID 1 (yg / ml) B. space LPS E.coli LPS S. typhimurlum LPS 0.1 8.5 ± 2.9 0.0 ± 0.6 0.0 ± 0 1 23.0 + 11.4 36.6 ± 7.5 9.8 ± 6.6 5 55.4 ± 8 65.0 ± 3.6 31.1 ± 7.0 10 63.1 ± 8 75.0 ± 3.4 37.4 ± 7.5 20 71.7 ± 5.8 81.0 ± 3.5 58.5 + 10.5 50 86.7 ± 4.3 92.6 ± 2.5 73.1 ± 9.1 Table 4: reduction by cationic peptides of TNF-a induced by LPS of E. col! in RA 264.7 cells. RAW 264.7 mouse macrophage cells were stimulated with 100 ng / ml E. coli 0111: B4 LPS in the presence of the indicated concentrations of cationic peptides for 6 hours. The concentrations of TNF-α released to the culture supernatants were determined by ELISA. Background levels of TNF-α production by RAW 264.7 cells cultured without stimuli for 6 hours resulted in TNF-α levels ranging from 0.037 to 0.192 ng / ml. The data are from duplicate samples and are presented as the average of three experiments plus the standard deviation.

Peptide (20 ug / ml) Inhibition of TNF-α (%) SEQ ID 5 65.6 ± 1.6 SEQ ID 6 59.8 ± 1.2 SEQ ID 7 50.6 ± 0.6 SEQ ID 8 39.3 ± 1.9 SEQ ID 9 58.7 ± 0.8 SEQ ID 10 55.5 ± 0.52 SEQ ID 12 52.1 ± 0.38 SEQ ID 13 62.4 ± 0.85 SEQ ID 14 50.8 ± 1.67 SEQ ID 15 69.4 ± 0.84 SEQ ID 16 37.5 ± 0.66 SEQ ID 17 28.3 ± 3.71 SEQ ID 19 69.9 ± 0.09 SEQ ID 20 66.1 + 0.78 SEQ ID 21 67.8 ± 0.6 SEQ ID 22 73.3 + 0.36 SEQ ID 23 83.6 ± 0.32 SEQ ID 24 60.5 ± 0.17 SEQ ID 26 54.9 ± 1.6 SEQ ID 27 51.1 ± 2.8 SEQ ID 28 56 ± 1.1 SEQ ID 29 58.9 + 0.005 SEQ ID 31 60.3 ± 0.6 SEQ ID 33 62.1 ± 0.08 SEQ ID 34 53.3 ± 0.9 SEQ ID 35 60.7 ± 0.76 SEQ ID 36 63 + 0.24 SEQ ID 37 58.9 ± 0.67 SEQ ID 38 54 ± 1 SEQ ID 40 75 + 0.45 SEQ ID 41 86 ± 0.37 SEQ ID 42 80.5 ± 0.76 SEQ ID 43 88.2 ± 0.65 SEQ ID 44 44.9 + 1.5 SEQ ID 45 44.7 ± 0.39 SEQ ID 47 36.9 ± 2.2 SEQ ID 48 64 + 0.67 SEQ ID 49 86.9 ± 0.69 SEQ ID 53 46.5 + 1.3 SEQ ID 54 64 ± 0.73 Table 5: reduction by SEQ ID NO: 1 of the production of IL-8 induced by LPS in A459 cells A459 cells were stimulated with increasing concentrations of the peptide SEQ ID NO: 1 in the presence of LPS (100 ng / ml E. coli 0111: B4) for 24 hours. The concentration of IL-8 in the culture supernatants was determined by means of ELISA.

Background levels of IL-8 from single cells were 0.172 ± 0.029 ng / ml. The data is presented as the average of three experiments plus the standard error.

Table 6: reduction by the peptide SEQ ID NO: 2 of IL-8 production induced by E. coli LPS in A549 cells Human epithelial cells A549 were stimulated with increasing concentrations of the peptide SEQ ID NO: 2 in the presence of LPS (100 ng / ml E. coli 0111: B4) for 24 hours. The concentration of IL-8 in the culture supernatants was determined by ELISA. The data is presented as the average of three experiments plus the standard error.

Table 7: reduction by the peptide SEQ ID NO: 2 of IL-8 induced by LPS of E. coli in human blood Whole human blood was stimulated with increasing concentrations of the peptide and E. coli 0111: B4 LPS for 4 hours. The human blood samples were centrifuged and the serum was removed and tested for IL-8 by ELISA. The data is presented as the average of two donors.

Table 8: reduction by the peptide SEQ ID NO: 1 of the TNF-α production induced by LPS from E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 g / ml peptide . The supernatant was collected and tested for TNF ~ OI levels by ELISA. The data represent the amount of TNF-resulting from duplicate cavities of macrophages derived from bone marrow incubated with LPS alone for 6 hours (1.1 + 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 + 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Table 9: Inhibition of TNF-α production induced by E. coli LPS by delayed addition of the peptide SEQ ID NO: 1 to A459 cells. The peptide (20 g / ml) was added to the increasing time points to cavities already contained human A549 epithelial cells and 100 ng / ral of E. coli 0111: B4 LPS. The supernatant was collected after 6 hours and tested for TNF-a levels by ELISA. The data is presented as the average of three experiments plus the standard error.

Table 10: Protection against lethal endotoxemia in CD-1 mice sensitized with galactosamine by the peptide SEQ ID NO: 1 CD-1 mice (9 weeks of age) were sensitized to endotoxin by three intra-peritoneal injections of galactosamine (20 mg in 0.1 my sterile PBS). Then toxic shock was induced by intra-peritoneal injection of E. coli 0111: B4 LPS (3) ig in 0.1 ml of PBS). The peptide, SEQ ID NO: 1 (200 μg / aton = 8 mg / kg), was injected into a separate intra-peritoneal site 15 minutes after the injection of LPS. The mice were monitored for 48 hours and the results were recorded.

Table 11: Protection against lethal endotoxemia in CD-1 mice sensitized with galactosamine by cationic peptides CD-1 mice (9 weeks of age) were sensitized to endotoxin by intra-peritoneal injection of galactosamine (20 mg in 0.1 ml of sterile PBS) . Then endotoxic shock was induced by intra-peritoneal injection of E. coli 0111: B4 LPS (2 ug in 0.1 ml of PBS). The peptide (200 ug / mouse = 8 mg / kg) was injected into a separate intraperitoneal site 15 minutes after the injection of LPS. The mice were monitored for 48 hours and the results were recorded.

Table 12: Protection against lethal endotoxemia in BAlB / c mice sensitized with galactosamine by cationic peptides BALB / c mice (8 weeks of age) were sensitized to endotoxin by intra-peritoneal injection of galactosamine (20 mg in 0.1 ml of sterile PBS). Then endotoxic shock was induced by intra-peritoneal injection of E. coli 0111: B4 LPS (2 μg in 0.1 ml of PBS). The peptide (200 g / mouse = 8 mg / kg) was injected into a separate intraperitoneal site 15 minutes after the injection of LPS. The mice were monitored for 48 hours and the results were recorded.

SEQ ID 38 2 ug 6 0 SEQ ID 41 2 ug 6 0 SEQ ID 44 2 ug 6 0 SEQ ID 45 2 g 6 0 Table 13: protection against lethal endotoxemia in BALB / c mice by the peptide SEQ ID NO: 1 BALB mice / c were injected intra-peritoneally with 400 pg of E. coli 0111: B4 LPS. Peptide was injected (200 ug / mouse = 8 mg / kg) in a separate intraperitoneal site and the mice were monitored for 48 hours and the results were recorded.

Table 14: Peptide inhibition of TNF-α production induced by S. aureus LTA Macrophage cells from RAW 264.7 mice were stimulated with 1 pg / ml LTA of S. aureus in the absence and presence of increasing concentrations of the peptide . The supernatant was collected and tested for TNF-a levels by ELISA. Background levels of TNF-a production by RAW 264.7 cells cultured without stimuli for 6 hours resulted in TNF-a levels ranging from 0.037 to 0.192 ng / ml. The data is presented as the average of three or more experiments plus the standard error.

Table 15: inhibition by TNF-α production peptide induced by unrooted lipoarabinomanana of Mycobacterlvun Mouse macrophage cells RAW 264.7 were stimulated with 1 pg / ml of AraLAM in the absence and presence of 20 ug / ml of peptide or polymyxin B. The supernatant was collected and tested for TNF-a levels by ELISA. Background levels of TNF-a production by RAW 264.7 cells cultured without stimuli for 6 hours resulted in TNF-α levels ranging from 0.037 to 0.192 ng / ml. The data are presented as the average inhibition of three or more experiments plus the standard error.

Example 3 Determination of Toxicity of Cationic Peptides The potential toxicity of the peptides was measured in two ways. First, the assay of cytotoxicity detection kit (Roche) (lactate dehydrogenase-LDH) was used. It is a colorimetric assay for the quantification of cell death and cell lysis, based on the measurement of LDH activity released from the cytosol of damaged cells into the supernatant. The enzyme LDH is a stable cytoplasmic enzyme present in all cells and is released into the supernatant of the cell culture when damage occurs to the plasma membrane. An increase in the amount of dead or damaged cells in the plasma membrane results in an increase in the activity of the LDH enzyme in the culture supernatant, as measured with an ELISA slide reader, OD490nm (the amount of color formed in the assay is proportional to the number of cells used). In this assay, human bronchial epithelial cells (16HBEol4, HBE) were incubated with 100 μg of peptide for 24 hours, the supernatant was removed and tested for LDH. The other assay used to measure the toxicity of the cationic peptides is the WST-1 assay (Roche). This assay is a colorimetric assay for the quantification of cell proliferation and cell viability, based on the cutting of the tetrazolium salt WST-1 by mitochondrial dehydrogenases in viable cells (a non-radioactive alternative to the assay of incorporation of [3H] -thymidine). In this assay, the HBE cells were incubated with 100 μg of the peptide for 24 hours, and then 10 μl / cavity of the cell proliferation reagent WST-1 was added. The cells were incubated with the reagent and the plate is then measured with an ELISA plate reader, OD490nm. The results shown below in Tables 16 and 17 show that most of the peptides are not toxic to the cells tested. However, four of the peptides of formula F (SEQ ID NOS: 40, 41, 42 and 43) did not induce membrane damage, as measured by both assays. Table 16: toxicity of cationic peptides, as measured by the LDH release assay HBE human bronchial epithelial cells were incubated with 100 ug / ml of peptide or polymyxin B for 24 hours. The LDH activity was determined in the supernatant of cell cultures. As a control for the release of 100% LDH, Triton X-100 was added. The data are presented as the mean ± the standard deviation. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Treatment LDH release (OD490nm) Control without cells 0.6 ± 0.1 Control with Triton X-100 4.6 ± 0.1 Control without peptide 1.0 ± 0.05 SEQ ID 1 1.18 ± 0.05 SEQ ID 3 1.05 ± 0.04 SEQ ID 6 0.97 ± 0.02 SEQ ID 7 1.01 ± 0.04 SEQ ID 9 1.6 ± 0.03 SEQ ID 10 1.04 ± 0.04 SEQ ID 13 0.93 ± 0.06 SEQ ID 14 0.99 ± 0.05 SEQ ID 16 0.91 ± 0.04 SEQ ID 17 0.94 + 0.04 SEQ ID 19 1.08 ± 0.02 SEQ ID 20 1.05 ± 0.03 SEQ ID 21 1.06 ± 0.04 SEQ ID 22 1.29 ± 0.12 SEQ ID 23 1.26 ± 0.46 SEQ ID 24 1.05 + 0.01 SEQ ID 26 0.93 ± 0.04 SEQ ID 27 0.91 ± 0.04 SEQ ID 28 0.96 ± 0.06 SEQ ID 29 0.99 ± 0.02 SEQ ID 31 0.98 ± 0.03 SEQ ID 33 1.03 ± 0.05 SEQ ID 34 1.02 ± 0.03 SEQ ID 35 0.88 + 0.03 SEQ ID 36 0.85 ± 0.04 SEQ ID 37 0.96 ± 0.04 SEQ ID 38 0.95 ± 0.02 SEQ ID 40 2.8 ± 0.5 SEQ ID 41 3.3 + 0.2 SEQ ID 42 3.4 ± 0.2 SEQ ID 43 4.3 ± 0.2 SEQ ID 44 0.97 + 0.03 SEQ ID 45 0.98 ± 0.04 SEQ ID 47 1.05 ± 0.05 SEQ ID 48 0.95 ± 0.05 SEQ ID 53 1.03 ± 0.06 Polymyxin B 1.21 ± 0.03 Table 17: toxicity of cationic peptides, measured by the assay WST-1 HBE cells were incubated with 100 pg / ml of peptide or polymyxin B for 24 hours and cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Treatment OD490nm Control without cells 0.24 ± 0.01 Control with Triton X-100 0.26 ± 0.01 Control without peptide 1.63 + 0.16 SEQ ID 1 1.62 ± 0.34 SEQ ID 3 1.35 ± 0.12 SEQ ID 10 1.22 ± 0.05 SEQ ID 6 1.81 ± 0.05 SEQ ID 7 1.78 ± 0.10 SEQ ID 9 1.69 ± 0.29 SEQ ID 13 1.23 + 0.11 SEQ ID 14 1.25 ± 0.02 SEQ ID 16 1.39 ± 0.26 SEQ ID 17 1.60 ± 0.46 SEQ ID 19 1.42 ± 0.15 SEQ ID 20 1.61 + 0.21 SEQ ID 21 1.28 ± 0.07 SEQ ID 22 1.33 ± 0.07 SEQ ID 23 1.14 ± 0.24 SEQ ID 24 1.27 ± 0.16 SEQ ID 26 1.42 ± 0.11 SEQ ID 27 1.63 ± 0.03 SEQ ID 28 1.69 ± 0.03 SEQ ID 29 1.75 ± 0.09 SEQ ID 31 1.84 ± 0.06 SEQ ID 33 1.75 ± 0.21 SEQ ID 34 0.96 ± 0.05 SEQ ID 35 1.00 ± 0.08 SEQ ID 36 1.58 ± 0.05 SEQ ID 37 1.67 ± 0.02 SEQ ID 38 1.83 ± 0.03 SEQ ID 40 0.46 ± 0.06 SEQ ID 41 0.40 ± 0.01 SEQ ID 42 0.39 ± 0.08 SEQ ID 43 0.46 ± 0.10 SEQ ID 44 1.49 ± 0.39 SEQ ID 45 1.54 ± 0.35 SEQ ID 47 1.14 ± 0.23 SEQ ID 48 0.93 ± 0.08 SEQ ID 53 1.51 ± 0.37 Polymyxin B 1.30 ± 0.13 emplo 4 Regulation of Polynucleotides by Cationic Peptides Polynucleotide arrays were used to determine the effect of the cationic peptides themselves on the transcriptional response of macrophages and epithelial cells. Mouse macrophage cells RAW 264.7, human bronchial (HBE) or human epithelial A549, were placed on slides in tissue culture dishes of 150 mm at a rate of 5.6 x 106 cells / dish, grown overnight, and then incubated with 50 μg / ml of peptide or medium only for 4 hours. After stimulation, the cells were washed once with PBS treated with diethyl pyrocarbonate, and detached from the dish using a cell scraper. Total RNA was isolated using Trizol (Gibco Life Technologies). The RNA bead was resuspended in RNase-free RNAse containing water (Ambion, from Austin, Texas, United States). The RNA was treated with -DNAsel (Clontech, from Palo Alto, California, United States) for one hour at 37 ° C. After adding a termination mixture (0.1 M EDTA [pH 8.0], 1 mg / ml glycogen), the samples were extracted once with phenol: chloroform: isoamyl alcohol (25: 24: 1), and once with chloroform. The RNA was then precipitated by adding 2.5 volumes of 100% ethanol and 1/10 volume of sodium acetate, pH. 5.2. The RNA was re-suspended in RNase-free water with RNAse inhibitor (Ambion) and stored at -70 ° C. RNA quality was determined by gel electrophoresis on a 1% agarose gel. The lack of contamination by genomic DNA was determined using the isolated RNA as a template for PCR amplification with primers specific for β-actin (5 '-GTCCCTGTATGCCTCTGGTC-3' (SEQ ID NO: 55) and 5 '-GATGTCACGCACGATTTCC-3f ( SEQ ID NO: 56)). Agarose gel electrophoresis and staining with ethidium bromide confirmed the absence of an amplicon after 35 cycles. Atlas cDNA expression arrays (Clontech, Palo Alto, California, United States), which consist of 588 selected mouse cDNA's, arranged in duplicate on positively charged membranes, were used for early polynucleotide array studies (Tables) 18, 19). Radiation-marinated 32P cDNA probes, prepared from 5] ig total RNA, were incubated with the arrays overnight at 71 ° C. The filters were extensively washed and then exposed to a phospho-imaging screen (Molecular Dynamics, Sunnyvale, California, United States) for three days at 4 ° C. The image was captured using a Molecular Dynamics PSI phospho-imager. Hybridization signals were analyzed using image analysis software Atlaslmage 1.0 (Clontech) and Excel (Microsoft, of Redmond, Washington, United States). The intensities of each spot were corrected according to the background and normalized levels with respect to differences in the marbling of the probes, using the average values for five polynucleotides observed to vary little between the stimulation conditions: β-actin, ubiquitin, S29 ribosomal protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and Ca2 + ligation protein. When the normalized hybridization intensity for a given cDNA was less than 20, a value of 20 was assigned to calculate the relationships and relative expression. The following arrays of polynucleotides used (Tables 21-26) were the human cDNA arrays of Resgen (genome identification number is PRHU03-S3), which consist of 7,458 human cDNAs arranged in duplicate. The probes were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Virtek slide reader. The image processing software (Imagene 4.1, Marina del Rey, California, United States) determines the average intensity, average intensities, and background intensities. Standardization and analysis were carried out by subtracting the average background intensity from the average intensity value determined by Imagene. The intensities of each point were normalized by taking the mean value of point intensity of the population of point values within a slide and comparing this value with values of all the slides in the experiment. The relative changes observed with cells treated with peptides compared to control cells can be found in the following tables. The other polynucleotide arrays used (Tables 27-35) were the arrays of human operons (genome identification number is PRHU04-S1), which consist of about 14,000 human oligos arranged in duplicate. Probes were prepared from 10 g of total RNA and marbeted with düTP marbed with Cy3 or Cy5. In these experiments, A549 epithelial cells were placed in 100m tissue culture dishes at 2.5 x 10 6 cells / dish. Total RNA was isolated using RNAqueous (Ambion). DNA contamination was removed with the DNA-free kit (Ambion). The probes prepared from the total RNA were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Perkin Elmer array scanner. The image processing software (Imagene 5.0, Marina del Rey, California, United States) determines the average point intensity, average intensities, and background intensities. A "home" program was used to remove the background. The program calculates the intensity below 10% for each sub-network and subtracts this value for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each point were normalized by taking the mean value of point intensity of the population of point values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide, as compared to control cells, can be found in the following tables. Semi-quantitative RT-PCR was carried out to confirm results of polynucleotide arrays. Samples of 1 μg of RNA were incubated with 1 μ? of oligodT (500 pg / ml) and 1 μ? of mixed dNTP material at 1 mM, in a volume of 12 μ? with water treated with DEPC at 65 ° C for 5 minutes in a thermo-cycler. 4 μ? of shock absorber First Strand 5X, 2 μ? of DTT 0.1 M, and 1 μ? of recombinant ribonuclease inhibitor RNaseOüT (40 units / μ?) and incubated at 42 ° C for 2 minutes, followed by the addition of 1 μ? (200 units) of Superscript II (Invitrogen, of Burlington, Ontario, Canada). Negative controls were generated for each RNA source using parallel reactions in the absence of Superscript II. Table 18: toxicity of the cationic peptides, measured by the WST-1 assay. HBE cells were incubated with 100 μg / ml of peptide or polymyxin B for 24 hours and cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Polynucleotide Function Intensity Ratio Number of cleotide / Poly Stimupeptide: Access Protein nucleotide laN Not Stimulated13 Etkl 20 43 M68513 PDGFRB 24 25 X04367 20 23 X72305 NOTCH4 48 18 M80546 IL-1R2 20 16 X59769 MCP-3 56 14 S71251 BMP-1 20 14 L24755 protein 20 14 U32329 c-ret 20 13 X67812 LIFR 20 12 D26177 B P-8a 20 12 M97017 Zfp92 87 11 U47104 MCSF 85 11 X05010 GCSFR 20 11 58288 IL-8RB 112 10 D17630 IL-9R 112 6 M84746 Cas 31 6 U48853 p58 / GTA 254 5 M58633 CASP2 129 5 D28492 IL-? ß pre91 5 M15131 cursor SPI2-2 62 5 M64086 C5AR 300 4 S46665 L-myc 208 4 X13945 IL-10 168 4 M37897 pl9ink4 147 4 U19597 ATOH2 113 4 U29086 DNAsel 87 4 U00478 CXCR-4 36 4 D87747 Ciclin D3 327 3 U43844 IL-7Ra 317 3 M29687 POLA 241 3 D17384 Tie-2 193 3 S67051 DNL1 140 3 U04674 BAD 122 3 L37296 GADD 5 88 3 L28177 Sik 82 3 U16805 integrina4 2324 2 X53176 TGFpRl 1038 2 D25540 LAMR1 1001 2 J02870 Crk 853 2 S72408 ZFX 379 2 M32309 Ciclin El 671 2 X75888 POLD1 649 2 Z21848 Vav 613 2 X64361 YY (NFE1 593 2 L13968 JunD 534 2 J050205 Csk 489 2 U05247 Cdk7 475 2 U11822 MLC1A 453 2 M19436 ERBB-3 435 2 L47240 UBF 405 2 X60831 TRAIL 364 2 U37522 LFA-1 340 2 X14951 SLAP 315 2 U29056 IFNGR 308 2 M28233 LIM-1 295 2 Z27410 ATF2 287 2 S76657 FST 275 2 Z29532 TIMP3 259 2 L19622 RU49 253 2 U41671 IGF-lRa 218 2 U00182 Ciclin G2 214 2 U95826 fyn 191 2 U70324 BMP-2 186 2 L25602 BM-3.2 POU 174 2 S68377 KIF1A 169 2 D29951 MRC1 167 2 Z11974 PAI2 154 2 X19622 BKLF 138 2 U36340 TIMP2 136 2 X62622 More 131 2 X67735 NURR-1 129 2 S53744 Table 19: toxicity of the cationic peptides, measured by the WST-1 assay. HBE cells were incubated with 100 μ / p.sup.1 of peptide or polymyxin B for 24 hours and cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Polynucleotide Function Intensity Ratio Number of cleotide / of the Poly- StimuPeptide: Access Protein nucleotide lada No Stimuladab channel 257 0.08 L36179 sodium XRCC1 227 0.09 U02887 ets-2 189 0.11 J04103 XPAC 485 0.12 X74351 EPOR 160 0.13 J04842 PEA 3 158 0.13 X63190 224 0.2 U11688 N- 238 0.23 M31131 OCT3 583 0.24 M34381 ??,? ß 194 0.26 U43144 KR 18 318 0.28 M11686 THAM 342 0.32 X58384 CD40L 66 0.32 X65453 CD86 195 0.36 L25606 1127 0.39 D31942 PMS2 DNA 200 0.4 U28724 IGFBP6 1291 0.41 X81584 ??? - 1ß 327 0.42 M23503 ATBF1 83 0.43 D26046 367 0.43 M96823 bcl-x 142 0.43 L35049 363 0.47 L33406 IL-12 P40 601 0.48 M86671 MmRad52 371 0.54 Z32767 Tobl 956 0.5 D78382 Ungí 535 0.51 X99018 KRT19 622 0.52 M28698 PLCy 251 0.52 X95346 287 0.54 X69902 GLÜTl 524 0.56 M23384 CTLA4 468 0.57 X05719 FRA2 446 0.57 X83971 MTRP 498 0.58 U34259 HBE cells were incubated with 100 ug / ml of peptide or polymyxin B for 24 hours and cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Table 20: toxicity of the cationic peptides, measured by the WST-1 assay. HBE cells were incubated with 100 μg / ml of peptide or polymyxin B for 24 hours and cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton was added X-100 Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Polynucleotide T-PCR Radio - * CXCR-4 4.0 ± 1.7 4.1 ± 0.9 IL-8RB 9.5 ± 7.6 7.1 ± 1.4 MCP-3 13.5 ± 4.4 4.8 + 0.88 IL-10 4.2 ± 2.1 16.6 ± 6.1 CD14 0.9 ± 0.1 0.8 ± 0.3 MIP-1B 0.42 ± 0.09 0.11 ± 0.04 XRCC1 0.12 ± 0.01 0.25 ± 0.093 MCP-1 Not in 3.5 ± 1.4 Table 21: toxicity of cationic peptides, measured by assay WST-1 HBE cells were incubated with 100 pg / ml of peptide or polymyxin B for 24 hours and cell viability was tested. The data is presented as the mean + the standard deviation.

As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Polynucleotide - IntensiRelation Peptide: No Number of do / Protein not Stimulated stimulated access ID 2 ID 3 ID 19 ID 1 0. 00 3086 1856 870 ?? 167887 0.53 2.5 1.6 1.9 3.1 ?? 486393 0.55 2.4 1.0 4.9 1.8 ?? 454657 0.54 2.1 2.0 1.5 1.9 AW029299 0.28 18 3.0 15 3.6 AA150416 33.71 3.0 0.02 H98636 1.00 5.3 4.50 0.8 AA194983 0.55 3.6 17 1.8 1.1 AA102526 0.75 1.3 2.3 0.8 4.6 AA894687 0.41 2.7 5.3 2.5 R56553 0.03 33 44 39 46 ?? 427521 0.50 3.1 2.0 1.7 3.3 R39227 0.03 33 44 39 46 AA427521 0.50 3.1 2.0 1.7 3.3 R39227 1.00 3.9 2.4 AI922341 0.90 2.4 2.1 0.9 1.1 AI473938 1.02 2.5 0.7 0.3 1.0 ?? 463248 0.14 4.5 7.8 6.9 7.8 N57964 0.25 4.0 3.9 3.9 5.1 R40400 0.05 7.9 20 43 29.1 AA497002 0.59 2.7 3.1 1.0 1.7 R22412 1.00 0.9 2.4 3.6 0.9 AA463257 0.94 0.8 2.5 1.9 1.1 ?? 424695 0.01 180 120 28 81 AA425451 0.47 2.1 2.1 7.0 2.6 W67174 0.55 2.7 2.8 1.8 1.0 AA037229 0.57 2.6 1.4 1.8 2.0 AA666269 0.65 0.8 2.2 4.9 1.5 AA485668 0.20 1.7 5.0 6.6 5.3 AI017019 0.21 2.8 4.7 9.7 6.7 AA487575 0.46 3.1 2.2 3.8 AA279188 0.94 1.1 2.3 3.6 0.5 H59231 0.49 1.5 2.1 3.3 2.2 AA043347 0.44 1.9 2.3 2.5 4.6 H11006 0.42 8.1 2.2 2.4 7.3 H9778 0.11 13 26 9.5 AI740827 0.09 14.8 11.5 2.6 12.4 AI652584 0.34 3.0 2.5 4.5 9.9 R89615 0.86 1.2 2.2 2.4 ?? 025276 0.50 0.4 2.0 4.4 3.0 AA629897 0.11 9.7 9.0 4.1 13.4 AA190627 1.00 3.2 1.0 0.9 1.3 W93370 0.95 2.3 1.7 0.7 1.1 AI433079 0.45 2.1 8.0 2.2 5.3 H70491 0.40 1.9 2.5 3.5 4.0 AA458507 1.00 1.7 2.3 0.4 0.7 AA1735458 0.72 1.9 2.8 0.3 1.4 15390 1.00 3.1 1.4 0.4 AA425767 1.00 2.6 0.9 1.2 0.9 ?? 927710 0.18 8.2 5.5 6.2 2.5 N39161 0.78 2.5 1.3 1.1 1.4 ?? 485226 0.54 6.1 1.9 2.2 AA454652 0.25 4.1 4.9 3.8 4.9 AA406362 1.03 2.5 1.0 0.5 0.8 R56211 1.00 3.1 2.0 AI057229 0.51 2.2 2.0 2.4 0.3 AA449831 1.00 6.9 16 W93891 0.41 3.1 1.8 4.0 2.5 N57553 0.83 2.0 2.3 1.0 1.2 AA863086 0.77 2.7 1.3 1.8 AA670107 0.65 7.2 6.0 1.5 AA972293 0.34 3.0 6.3 2.9 R24266 0.61 1.6 2.4 8.3 AA037376 0.22 26 4.5 2.6 18.1 AA521362 0.07 12 14 14 16 7? 7? 450009 0.56 11 12 1.8 AA704511 0.12 7.8 8.5 10 8.7 AI936324 0.40 7.3 5.0 1.6 2.5 N94921 1.02 1.0 13.2 0.5 0.8 AA682684 0.28 3.5 4.0 0.9 5.3 AA434420 0.42 2.9 2.4 2.2 3.0 AA995560 1.00 2.3 2.2 0.8 0.5 AA446259 0.58 1.7 2.4 3.6 1.7 AA679180 0.52 3.2 0.9 1.9 6.5 AI668897 0.25 4.0 2.4 16.8 12.8 H82419 0.60 3.6 3.2 1.6 1.0 AA045326 0.73 1.2 2.8 3.0 1.4 R52794 0.20 6.1 1.2 5.6 5.0 AA644448 1.00 5.1 2.4 AA481547 0.45 2.8 2.2 1.9 2.2 AA086038 0.52 2.1 2.7 1.1 1.9 W68281 0.10 18 9.6 32 H07920 1.00 3.0 5.2 0.8 0.2 W69649 0.09 11.5 12 33 H39192 0.49 2.1 1.7 2.2 2.0 AI936909 0.40 3.7 3.0 2.4 2.5 AI719098 0.05 19 19 27 AA460530 0.08 19 15 12 N58443 0.26 5.2 3.1 7.1 3.9 H84878 0.20 6.8 5.4 4.9 5.0 N62306 0.02 48 137 82 AI264190 0.27 3.7 8.9 10.6 R39932 1.00 1.9 5.2 AA291323 0.56 2.8 1.6 2.4 1.8 AI972925 0.79 0.7 2.6 1.3 2.8 W45688 0.46 2.2 1.4 2.3 2.9 AA521316 0.95 2.2 1.0 0.6 2.0 AA448468 Table 22: toxicity of the cationic peptides, measured by the WST-1 assay. HBE cells were incubated with 100 peptide or polymyxin B for 24 hours and the cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Polynucleó- IntensiRelación Peptide: No EsNumero de tido / Projeto no fibulada Acceso teína Stimulada ID 2 ID 3 ID 19 ID 1 TLR1 3.22 0.35 0.31 0.14 0.19 AI339155 TLR2 20.9 0.52 0.31 0.48 0.24 T57791 TLR5 8.01 0.12 0.39 N41021 TLR7 503 0.13 0.11 0.20 0.40 N30597 TNF 0.82 1.22 0.45 2.50 2.64 T55353 TNF 3.15 0.15 0.72 0.32 ?? 504259 TNF 4.17 0.59 0.24 0.02 W71984 TNF R 2.62 0.38 0.55 0.34 AA987627 1.33 0.75 0.22 0.67 0.80 AA488650 1.39 0.34 0.72 1.19 0.34 AA464526 2.46 0.41 0.33 0.48 0.58 AA903183 3.34 0.30 0.24 0.48 N54821 4.58 0.67 0.22 AA977194 1.78 0.50 0.42 0.92 0.56 AA482489 2.42 0.91 0.24 0.41 0.41 0.41 0.41 H62473 1.00 1.38 4.13 0.88 AI982606 2.26 0.32 0.44 1.26 AA495985 2.22 0.19 0.38 0.45 0.90 AI285199 2.64 0.38 0.31 1.53 AA916836 3.57 0.11 0.06 0.28 '0.38 AI889554 2.02 0.50 1.07 0.29 0.40 AA878880 2.84 1.79 0.32 0.35 AA677522 2.70 0.41 0.37 0.37 0.34 ?? 489234 1.94 0.46 0.58 0.51 0.13 AI761788 2.00 0.23 0.57 0.30 0.50 AA136983 2.11 0.43 0.53 0.10 0.47 AA425217 1. 67 0.42 0.41 1.21 0.60 H39187 1.78 0.37 0.40 0.56 0.68 R41787 4.43 0.03 0.23 0.61 H00662 1.40 0.20 0.72 0.77 0.40 H16591 1.00 0.12 0.31 2.04 1.57 AA479188 2.42 0.41 0.26 0.56 AA450324 2.53 0.57 0.39 0.22 0.31 AA055979 1.16 0.86 0.05 0.01 2.55 AA865557 1.00 0.33 0.18 1.33 2.25 AA460959 1.00 0.32 1.52 1.90 0.06 AA434397 3.27 0.10 1.14 0.31 0.24 56754 2.50 0.40 0.29 0.57 0.57 0.17 AI205675 2.11 0.32 0.63 0.47 0.35 AA398492 1.62 0.39 0.42 1.02 0.62 AI375048 1.00 0.41 1.24 1.14 0.45 AI453185 1.62 0.49 0.85 0.62 0.15 R45640 2.31 0.43 0.31 0.23 0.54 H73241 3.85 -0.20 0.26 0.76 0.02 H20822 1.63 0.27 0.06 1.21 0.62 R68106 1. 78 0.43 0.00 0.56 0.84 AI676097 2.25 0.44 0.05 0.38 0.99 N63398 14.21 1.10 0.07 AI815229 2.31 0.75 0.43 0.19 0.40 AA076350 1.67 0.35 0.60 0.18 0.90 H54023 1.18 0.38 0.85 0.87 0.26 AI739498 2.19 0.43 1.06 0.46 N49751 1.55 0.44 0.64 0.30 0.81 H74265 2.08 0.23 0.37 0.56 0.48 AA464542 2.27 0.02 0.44 0.64 AA464590 2.34 0.11 0.43 0.24 0.89 AI924306 1.59 0.63 0.34 0.72 0.35 AA476461 1.07 0.94 0.43 0.25 1.13 H03504 1.70 0.07 0.85 0.47 0.59 AA418293 1.27 0.37 0.79 1.59 -5.28 AA402447 1.00 0.34 0.66 2.10 1.49 W61116 2.90 0.16 0.35 0.24 0.55 AI202738 1.48 0.20 0.91 0.58 0.68 AA053674 2.21 0.45 0.20 1.03 0.41 AA043537 2.62 0.37 0.38 0.70 A 084649 1.04 0.96 0.09 0.29 2.79 AA417711 1.53 0.65 0.41 0.99 0.44 R80779 1.32 1.23 0.27 0.50 W56266 0.52 2.13 2.68 0.13 1.93 68281 0.84 1.20 3.25 0.02 1.31 AA425826 1.00 0.97 1.62 7.46 AA460969 0.09 11.45 11.80 33.43 H39192 0.10 17.83 9.61 32.30 H07920 3.7397 0.27 0.06 0.68 0.18 AA668470 1.8564 0.54 0.45 0.07 1.09 H70047 1.04 1.84 0.16 0.09 0.96 R91916 1.78 0.32 0.56 0.39 0.77 AI953187 2.62 0.34 0.91 0.38 ?? 488413 7.16 1.06 0.10 0.11 0.14 AI131555 1.00 0.28 2.50 1.28 0.19 AI439571 2.83 0.44 0.33 0.35 T95052 1. 00 1.07 0.35 1.91 0.08 AA496348 Table 23: toxicity of the cationic peptides, measured by the WST-1 assay. HBE cells were incubated with 100 pg / ml of peptide or polymyxin B for 24 hours and cell viability was tested. The data are presented as the mean ± the standard deviation. As a control for 100% LDH release, Triton X-100 was added. Only the peptides SEQ ID NOS: 40, 41, 42 and 43 showed some significant toxicity.

Table 24: Reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coll LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide. The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-c resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Polynucleotide - IntentRelation Peptide: Not Stimulated Number of tido / Proximity Theine access; Funnum Stimulation ID 2 ID 3 ID 19 ID 1 from 3.22 0.35 0.31 0.14 0.19 AI339155 2.09 0.52 0.31 0.48 0.24 T57791 8.01 0.12 0.39 N41021 5.03 0.13 0.11 0.20 0.40 N30597 0.82 1.22 0.45 2.50 2.64 T55353 3.15 0.15 0.72 0.32 AA504259 4.17 0.59 0.24 0.02 W71984 2. 62 0.38 0.55 0.34 0.98 0.98 0.32 0.44 0. 0.26 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0 0.28 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0 0. 0 0. 0.38 0.38 AI889554 2.02 0.50 1.07 0.29 0.40 AA878880 2.84 1.79 0.32 0.35 AA677522 4.58 0.67 0.22 AA977194 1.78 0.50 0.42 0.92 0.56 AA482489 4.43 0.03 0.23 0.61 0.69 H00662 1.40 0.20 0.72 0.77 0.40 H16591 1.00 0.12 0.31 2.04 1.57 AA479188 2.42 0.41 0.26 0.56 AA450324 0.00 3085.96 1855.90 869.57 AI167887 0.53 2.51 1.56 1.88 3.10 AA486393 0.28 17.09 3.01 14.93 3.60 AA150416 33.71 2.98 0.02 H98636 1.00 5.29 4.50 0.78 ??? 194983 0.50 3.11 2.01 1.74 3.29 R39227 0.90 2.38 2.08 0.87 1.11 ?? 473938 1.00 2.62 0.87 1.15 0.88 AA927710 Table 25: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide. The supernatant was collected and tested for TNF- levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 + 0.012 ng / ml for 24 hours.

Polynucleotide- IntentRelation Peptide: Not Stimulated Number of thido / Prositicity Access theine; Funno Escion timulaID 2 ID 3 ID 19 ID 1 da 0.00 3085.96 1855.90 869.57 ?? 167887 0.53 2.51 1.56 1.88 3.10 AA486393 0.28 17.09 3.01 14.93 3.60 ?? 150416 33.71 2.98 0.02 H98636 1.00 5.29 4.50 0.78 AAA194983 0.50 3.11 2.01 1.74 3.29 R39227 0.90 2.38 2.08 0.87 1.11 AI473938 1.00 2.62 0.87 1.15 0.88 AA927710 Table 26: reduction by peptide SEQ ID NO: 1 of the TNF-at production induced by LPS of E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml peptide . The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Table 27: reduction by peptide SEQ ID NO: 1 of TNF-a production induced by LPS from E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide . The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Gene (Accession Number) Control: Unstimulated Peptide Ratio Cells treated: control 0.69 9.3 26.3 8.2 0.65 7.1 0.93 6.9 0.84 5.9 0.55 5.6 0.55 5.4 0.62 5.0 0.69 4.8 0.66 4.4 0.55 4.2 0.73 4.2 6. 21 4.0 0.89 4.0 1.74 4.0 0.70 4.0 0.59 3.9 0.87 3.8 0.63 3.8 0.69 3.8 0.71 3.7 0.67 3.6 0.67 3.5 0.56 3.5 1.35 3.4 0.68 3.4 0.80 3.4 2.02 3.4 1.04 3.3 0.80 3.3 0.74 3.2 0.65 3.2 0.70 3.2 0.81 3.0 0.78 3.0 1.03 2.9 0.80 2.9 0.95 2.9 3.39 2.9 2.08 2.9 7.16 2.9 0.79 2.8 1.09 2.8 0.84 2.8 1.01 2.8 0.86 2.7 15.33 2.7 0.73 2.7 0.70 2.5 0.61 2.4 0.76 2.4 0.95 2.4 0.67 2.3 0.89 2.2 1.67 2.2 1.21 2.2 0.96 2.1 1.10 2.1 1.47 2.1 0.50 2.1 1.46 2.0 0.89 2.0 Table 28: reduction by the peptide SEQ ID NO: 6 of the TNF-a production induced by LPS from E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 g / ml peptide .

The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of T F-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Gen (Number of AcceControl: Cells Peptide Ratio so) Not Stimulated treated: control 17 0.06 2.0 0.13 1.1 0.13 13 0.14 8.6 0.14 1.2 0.15 0.9 0.17 0.9 0.19 1.5 0.21 0.7 0.22 0.9 0.23 0.8 0.26 1.1 0.28 0.7 0.29 1.7 0.29 3.3 0.30 3.8 0.31 2.9 0.31 1.0 0.32 0.8 0.32 5.5 0.32 1.0 0.32 1.5 0.33 1.5 0.34 0.5 0.35 3.0 0.35 1.3 0.35 0.7 0.35 13 0.35 1.6 0.35 46 0.36 7.4 0.37 1.8 0.37 1.1 0.37 1.3 0.38 5.2 0.38 1.3 0.38 0.7 0.40 5.6 0.41 5.3 0.42 14 0.44 1.8 0.44 1.3 0.44 15 0.45 1.7 0.46 1.1 0.46 2.2 0.46 16 0.46 3.9 0.46 287 0.47 1.4 0.48 0.6 0.49 2.6 0.49 1.8 0.49 2.1 0.49 2.4 0.49 2.5 0.49 Table 29: reduction by the peptide SEQ ID NO: 1 of the production of TNF-a induced by LPS of E coll in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 g / ml of the peptide. The supernatant was collected and tested for TNF- levels by ELISA. The data represent the amount of TNF-α resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 + 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Gen Control Number: Access CéRelación Cells no EsPéptula treated treated: control AL110161 0.22 5218.3 AF131842 0.01 573.1 AJ000730 0.01 282.0 Z25884 0.01 256.2 M93426 0.01 248.7 X65857 0.01 228.7 M55654 0.21 81.9 AK001411 0.19 56.1 D29643 1.56 55.4 AF006822 0.07 55.3 AL117601 0.05 53.8 AL117629 0.38 45.8 M59465 0.50 45.1 AB013456 0.06 41.3 AJ131244 0.56 25.1 AL110179 0.87 24.8 AB037844 1.47 20.6 A47727 0.11 20.5 AL035694 0.81 20.4 X68994 0.13 19.3 AJ238379 1.39 18.5 N _003519 0.13 18.3 U16126 0.13 17.9 Ü29926 0.16 16.3 AK001160 0.39 14.4 U18018 0.21 12.9 D80006 0.21 12.6 AK000768 0.30 12.3 X99894 0.26 12.0 AL031177 1.09 11.2 AF052091 0.28 10.9 L38928 0.22 10.6 AL117421 0.89 .10.1 AL133606 0.89 9.8 NM_016227 0.28 9.6 NM_006594 0.39 9.3 U54996 0.59 9.3 AJ007557 0.28 9.0 AF043938 1.24 8.8 AK001607 2.74 8.7 AL031320 0.31 8.4 D38024 0.31 8.3 AF059575 2.08 8.2 AF043724 0.39 8.1 AK002062 2.03 8.0 L13436 0.53 7.8 U33749 0.36 7.6 AF011792 0.31 7.6 AK000193 1.18 6.8 AF039022 0.35 6.8 17017 0.50 6.7 AF044958 0.97 6.5 U35246 0.48 6.5 AK001326 1.59 6.5 55422 0.34 6.4 U44772 1.17 6.3 AL117485 0.67 5.9 AB037776 0.75 5.7 AF131827 0.69 5.6 AL137560 0.48 5.2 X05908 0.81 5.1 X68264 0.64 5.0 AL161995 0.86 4.9 AF037372 0.48 4.8 M 016187 0.65 4.8 AL137758 0.57 4.8 U59863 0.46 4.7 Z30643 0.70 4.7 D16294 1.07 4.6 AJ132592 0.55 4.6 X82324 1.73 4.5 NMJ316047 1.95 4.5 AK001371 0.49 4.5 M60746 30.5 4.5 AB033071 4.47 4.4 AB002305 1.37 4.4 X92689 0.99 4.4 AL049543 1.62 4.3 U43148 0.96 4.3 M67439 2.61 4.2 U09850 0.56 4.2 L20316 0.75 4.2 AB37767 0.69 4.2 NM_017433 99.20 4.2 D26579 0.59 4.1 L10333 1.81 4.1 AK000761 1.81 4.1 U91540 0.80 4.1 Z17227 0.75 4.0 Table 30: reduction by the peptide SEQ ID NO: 1 of the TNF-OI production induced by LPS of E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml peptide . The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Gen Control Number: Cell Access Code not ESSE ID NO: l Timed treated: control AC004908 32.4 0.09 S70622 43.1 0.10 Z97056 12.8 0.11 AK002056 11.4 0.12 L33930 28.7 0.13 X77584 11.7 0.13 NM 014106 25.0 0.14 M37583 22.2 0.14 U89387 10.2 0.14 D25274 10.3 0.15 J04173 11.4 0.15 U19765 8.9 0.16 X67951 14.1 0.16 AL096719 20.0 0.16 AF165217 14.6 0.16 M 014341 11.1 0.16 AL022068 73.6 0.17 X69150 42.8 0.17 AL031577 35.0 0.17 AL031281 8.9 0.17 AF090094 10.3 0.17 AL022723 20.6 0.18 U09813 9.8 0.18 AF000560 20.2 0.19 NM_016094 67.2 0.19 AF047183 7.5 0.19 D14662 8.1 0.19 X16662 8.5 0.19 Ü14588 11.3 0.19 AL117654 12.6 0.20 A 001962 7.7 0.20 L41559 9.1 0.20 NM_016139 21.0 0.21 NM_016080 10.7 0.21 U86782 6.7 0.21 AJ400717 9.8 0.21 X07495 31.0 0.21 AL034410 7.3 0.22 X14787 26.2 0.22 AF081192 6.8 0.22 D49489 11.0 0.22 NM_014051 9.3 0.22 AK001536 98.0 0.22 X62534 9.5 0.22 AJ005259 6.7 0.22 NM_000120 10.0 0.22 M38591 23.9 0.23 AF071596 11.5 0.23 X16396 8.3 0.23 AK000934 7.6 0.23 AL117612 10.7 0.23 AF119043 7.3 0.23 AF037066 7.6 0.23 AF134406 13.3 0.23 AE000661 9.2 0.24 AL157424 7.2 0.24 X56468 7.2 0.24 U39318 10.7 0.24 AL034348 24.4 0.24 D26600 11.4 0.24 AB032987 16.7 0.24 J04182 7.4 0.24 X78925 16.1 0.25 NM_000805 38.1 0.25 U29700 12.0 0.25 Z98200 13.4 0.25 U07857 10.3 0.25 L05096 25.3 0.25 AK001443 7.5 0.25 K03515 6.2 0.25 X57352 7.5 0.26 J02883 5.7 0.26 M24069 6.3 0.26 AJ269537 60.5 0.26 AL137555 8.5 0.26 U89505 5.5 0.26 U82938 7.5 0.26 X99584 12.8 0.26 AK000847 35.8 0.27 NM_014463 7.8 0.27 AL133645 '50.8 0.27 X78924 13.6 0.27 NM_004304 15.0 0.27 X57958 27.9 0.27 U63542 12.3 0.27 AK000086 8.3 0.27 X57138 32.0 0.27 AB023206 6.5 0.27 AB021641 5.5 0.28 AF050639 5.5 0.28 M62505 7.5 0.28 X64364 5.8 0.28 AJ224082 22.5 0.28 AF042165 20.4 0.28 AK001472 10.9 0.28 X86428 12.7 0.28 AF227132 5.1 0.28 Z98751 5.3 0.28 D21260 8.3 0.28 AF041474 15.1 0.28 NM_005258 7.6 0.28 L20859 9.6 0.29 Z80783 9.0 0.29 AB011105 7.1 0.29 AL008726 5.2 0.29 D29012 12.6 0.29 X63629 6.8 0.29 X02419 12.9 0.29 X13238 8.0 0.29 X59798 12.7 0.30 D78151 7.6 0.31 AF054185 18.8 0.31 J03890 5.5 0.32 M34079 5.2 0.33 Table 31: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in murine bone marrow macrophages Bone marrow-derived macrophages of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / inl of the peptide. The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Control number of contr Controls ID 5: ID 6: ID ID ID access ID rol- ol- concon7: 8: 9: 10: Cy3 Cy5 trol trol withcontrol trol trol control UI12472 0.09 0.31 13.0 3.5 4.5 7.0 4.3 16.4 X66403 0.17 0.19 7.8 9.9 6.0 6.4 5.0 15.7 ?? 001932 0.11 0.25 19.4 4.6 9.9 7.6 8.1 14.5 X58079 0.14 0.24 12.2 7.6 8.1 4.3 4.5 13.2 U18244 0.19 0.20 6.1 9.7 11.9 5.0 3.7 10.6 U20648 0.16 0.13 5.3 6.2 5.6 3.1 6.8 9.5 AB037832 0.10 0.29 9.0 4.2 9.4 3.1 2.6 8.7 AC002542 0.15 0.07 10.5 15.7 7.8 10.1 11.7 8.2 M89796 0.15 0.14 2.6 6.1 7.6 3.5 13.3 8.1 AF042163 0.09 0.19 3.9 3.2 7.6 6.3 4.9 7.9 AL032821 0.41 0.23 2.5 5.2 3.2 2.1 4.0 7.9 U25341 0.04 0.24 33.1 5.1 23.3 6.6 4.1 7.6 U52219 0.28 0.20 2.1 6.2 6.9 2.4 3.9 7.1 X04506 0.29 0.32 7.9 3.4 3.3 4.8 2.6 7.0 AB011138 0.12 0.07 3.5 12.9 6.6 6.4 21.3 6.9 AF055018 0.28 0.22 3.8 6.9 5.0 2.3 3.1 6.8 AK002037 0.08 0.08 2.9 7.9 14.1 7.9 20.1 6.5 AK001024 0.16 0.11 7.7 11.9 5.0 10.3 6.0 6.3 AF240467 0.11 0.10 20.4 9.0 3.4 9.4 12.9 6.1 AF105367 0.15 0.35 23.2 2.6 3.0 10.6 2.9 5.7 AL009183 0.46 0.19 10.6 4.7 3.7 2.8 6.5 5.7 X54380 0.23 0.08 4.7 11.9 7.2 12.7 3.8 5.5 AL137736 0.22 0.15 2.1 7.2 3.3 7.1 4.6 5.5 X05615 0.28 0.42 6.3 2.7 7.7 2.4 3.1 5.4 D28114 0.24 0.08 2.5 15.9 13.0 7.1 13.7 5.4 A 000358 0.28 0.28 8.7 4.2 7.2 3.2 2.4 5.3 AK001351 0.12 0.22 3.9 7.6 8.7 3.9 2.3 5.2 U79289 0.14 0.27 2.5 2.7 2.8 2.0 4.3 5.1 AB14546 0.12 0.34 6.8 2.4 4.1 2.7 2.0 5.0 AL117428 0.10 0.07 2.8 16.1 12.8 9.7 14.2 4.9 AL050378 0.41 0.14 3.5 8.7 11.7 3.5 7.0 4.9 AJ250562 0.13 0.10 5.2 5.7 14.2 3.8 10.3 4.8 N _001756 0.28 0.13 4.0 7.9 6.5 14.9 5.6 4.8 AL137471 0.29 0.05 3.7 18.0 6.2 7.2 16.3 4.7 M19684 0.41 0.14 3.5 4.6 5.4 2.8 9.4 4.7 NM_001963 0.57 0.05 3.4 6.2 1.8 32.9 14.7 4.4 N _000910 0.62 0.36 3.1 2.7 2.3 2.6 3.1 4.4 AF022212 0.19 0.02 9.0 45.7 25.6 12.4 7.22 4.4 A 001674 0.11 0.13 8.4 6.5 7.9 4.5 7.4 4.3 U51920 0.23 0.27 3.4 3.8 2.1 4.1 8.8 4.2 A 000576 0.27 0.06 4.4 14.7 7.4 14.1 8.6 4.2 AL080073 0.17 0.20 21.6 3.9 4.3 8.8 2.6 4.1 U59628 0.34 0.06 3.4 14.1 5.4 7.9 4.9 4.1 U90548 0.41 0.31 2.3 4.7 5.5 6.8 3.4 4.1 19673 0.43 0.26 2.3 8.5 4.5 2.5 4.1 3.8 AL161972 0.44 0.37 2.0 3.6 2.0 2.7 5.5 3.8 X54938 0.32 0.22 3.9 3.3 6.2 3.1 4.4 3.7 ?? 014575 0.04 0.13 46.2 4.5 10.2 8.0 6.2 3.4 M83664 0.57 0.29 2.9 2.1 2.0 3.1 6.6 3.4 AK000043 0.34 0.14 2.7 7.1 3.7 9.4 8.8 3.3 U60666 0.21 0.11 9.9 9.0 4.1 5.5 13.0 3.3 AK000337 0.49 0.19 4.3 5.1 4.7 10.6 7.1 3.3 AF050198 0.34 0.15 7.0 6.3 3.6 5.6 11.9 3.3 AJ251029 0.28 0.12 4.4 9.4 7.2 8.8 7.1 3.2 X74142 0.12 0.33 19.5 4.5 8.4 6.4 4.4 3.2 AB029033 0.35 0.24 3.1 2.2 5.6 5.2 3.1 3.1 D35606 0.51 0.14 4.3 3.9 4.6 3.5 7.2 3.1 X84195 0.32 0.19 4.8 3.7 5.0 11.2 9.8 3.0 057971 0.29 0.13 2.2 7.9 1.8 6.3 4.8 3.0 J02611 0.28 0.10 2.8 11.0 3.7 10.3 8.4 3.0 AF071510 0.07 0.05 7.9 3.8 11.7 46.0 16.3 3.0 AF131757 0.10 0.08 4.8 9.0 44.3 9.3 10.7 3.0 L10717 0.45 0.21 2.5 4.9 2.8 10.9 4.5 2.9 L32961 0.64 0.32 3.6 2.9 3.2 5.3 2.3 2.9 AL157466 0.05 0.06 18.0 21.4 16.7 5.2 6.8 8.6 AB023215 0.19 0.07 14.8 10.6 7.9 14.4 6.6 16.1 AL031121 0.24 0.09 14.1 5.7 3.8 5.5 2.8 4.6 NM_016331 0.16 0.08 12.8 7.2 11.0 5.3 11.2 9.7 M14565 0.16 0.12 10.6 12.5 5.0 3.6 10.1 6.3 U22492 0.28 0.07 10.4 8.9 4.8 10.8 6.6 3.6 U76010 0.14 0.07 9.7 18.6 3.7 4.8 5.6 8.9 AK000685 0.51 0.10 9.0 3.1 2'.8 3.9 15.3 3.0 AF013620 0.19 0.18 8.5 2.6 6.2 5.7 8.2 3.8 ALO 49296 0.61 0.89 8.1 3.2 2.7 3.2 2.7 2.0 AB006622 0.47 0.28 7.5 5.0 2.8 11.1 5.5 4.6 X04391 0.22 0.13 7.2 16.7 2.7 7.7 6.1 5.9 AK000067 0.80 0.35 7.1 4.6 2.1 3.2 8.5 2.2 AF053712 0.17 0.08 6.9 17.7 3.0 6.2 12.3 5.2 X58079 0.14 0.24 6.7 6.7 5.9 6.5 5.3 2.5 M91036 0.48 0.36 6.7 14.2 2.1 2.9 2.7 4.8 AF055018 0.28 0.22 6.3 10.7 2.7 2.6 4.6 6.5 L17325 0.19 0.29 6.1 4.4 6.5 4.7 4.0 4.0 D45399 0.21 0.18 6.1 4.6 5.0 2.8 10.8 4.0 AB023188 0.29 0.13 5.9 10.6 3.6 3.4 10.6 7.2 N _012177 0.26 0.31 5.9 5.5 3.8 2.8 3.0 6.8 D38550 0.43 0.39 5.8 3.4 2.1 4.5 2.5 2.4 AL050219 0.26 0.04 5.7 17.0 3.1 9.2 30.3 16.1 AL137540 0.67 0.79 5.5 3.2 3.9 10.9 2.9 2.3 D50926 0.57 0.21 5.4 5.6 2.0 3.3 4.4 3.2 AL137658 0.31 0.07 5.4 12.1 2.6 10.8 3.9 8.6 U21931 0.48 0.14 5.4 4.1 2.9 3.6 6.0 3.2 AK001230 0.43 0.26 5.0 4.6 2.1 2.2 2.5 2.7 AL137728 0.67 0.47 5.0 5.9 2.2 6.8 5.9 2.1 AB022847 0.39 0.24 4.5 2.2 3.5 4.3 3.8 3.7 X75311 0.67 0.22 4.3 4.0 2.0 8.3 4.0 5.1 AK000946 0.36 0.29 4.1 3.8 3.9 5.4 25.8 2.7 AB023197 0.25 0.30 4.0 8.3 2.1 8.8 2.2 4.9 AB014615 0.19 0.07 3.9 3.3 7.0 3.4 2.2 7.7 X04O14 0.29 0.16 3.8 2.5 2.2 3.0 5.5 3.1 U76368 0.46 0.17 3.8 3.8 2.8 3.2 4.2 3.0 AB032436 0.14 0.21 3.8 2.7 6.1 3.2 4.5 2.6 AB020683 0.37 0.21 3.7 4.2 2.2 5.3 2.9 9.4 NM_012126 0.31 0.20 3.7 5.2 3.2 3.4 3.9 2.5 AK002037 0.08 0.08 3.7 17.1 4.6 12.3 11.0 8.7 X78712 0.17 0.19 3.6 2.5 4.5 5.3 2.2 3.3 NM_014178 0.23 0.12 3.5 8.4 2.9 6.9 14.4 5.5 AC004079 0.31 0.11 3.5 7.0 2.1 2.0 7.3 9.1 AL080182 0.51 0.21 3.4 3.5 2.2 2.1 2.9 2.4 91036 0.22 0.02 3.4 26.3 5.8 6.8 30.4 21.6 AJ000512 0.27 0.43 3.3 2.1 4.9 2.3 3.9 2.7 AK002140 0.28 0.14 3.3 9.9 2.8 2.1 16.6 7.2 AL137284 0.22 0.04 3.3 7.2 4.1 6.0 12.2 3.7 Z11898 0.12 0.29 3.2 3.7 8.2 2.5 6.6 2.2 AB017016 0.27 0.29 3.1 2.8 2.5 2.8 3.3 5.5 X54673 0.34 0.08 2.9 12.0 2.2 10.4 7.4 5.9 AL033377 0.40 0.22 2.6 2.6 2.6 2.3 4.5 2.2 X85740 0.34 0.05 2.6 2.3 2.6 2.5 12.5 5.2 AB010419 0.59 0.20 2.5 12.8 2.0 2.8 2.9 5.9 AL109726 0.14 0.15 2.3 9.0 4.3 4.4 2.6 3.7 NM_012450 0.15 0.10 2.2 3.1 8.2 9.9 4.7 5.9 J04599 0.39 0.30 2.1 3.3 6.6 2.2 2.7 5.4 A 000266 0.49 0.35 2.1 3.5 3.5 6.6 4.3 4.0 Table 32: reduction by peptide SEQ ID NO: 1 of TNF-induced production of E. coll LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide. The supernatant was collected and tested for TNF-OI levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Number of Gene cont Contr ID ID ID ID ID D access role- 19: 20: 21: 22: 23: 24: Cy3 Cy5 conconconconcontrol trol trol trol trol trol trol AL157466 0.10 0.39 8.7 2.2 11.3 9.9 3.0 2.1 AL050125 0.23 0.07 8.6 14.3 5.2 2.8 18. 8.3 7 ?? 011096 0.21 0.08 8.5 24.4 4.7 6.8 10. 7.5 4 J03068 0.54 0.21 8.3 2.4 2.2 4.1 3.0 6.0 33906 0.14 0.08 7.6 4.5 15.2 6.1 7.5 7.9 AJ272265 0.21 0.09 7.6 9.0 3.3 4.9 18. 14.5 8 J00210 0.41 0.07 7.2 15.0 2.8 3.1 11. 4.3 0 AK001952 0.42 0.21 6.9 4.9 2.5 3.1 7.6 4.5 X54131 0.09 0.20 6.4 6.5 7.7 15.0 5.6 4.1 AF064493 0.46 0.14 5.9 5.6 2.2 2.9 8.5 5.8 AL117567 0.44 0.22 5.8 3.3 2.9 2.3 5.7 14.9 L40933 0.16 0.03 5.6 11.0 4.8 3.5 8.5 76.3 M27190 0.19 0.28 5.3 3.0 3.8 3.6 5.8 3.6 AL031121 0.24 0.09 5.3 3.8 3.2 3.9 3.0 27.9 U27655 0.24 0.29 5.0 9.0 4.5 8.3 4.2 4.5 AB037786 0.12 0.03 4.7 54.1 2.8 2.3 2.2 11.0 X73113 0.29 0.13 4.7 6.5 6.0 2.4 6.7 6.3 AB010962 0.08 0.12 4.7 6.2 2.4 4.7 10. 4.2 9 AL096729 0.36 0.13 4.7 7.7 3.2 2.4 6.3 6.2 AB018320 0.16 0.18 4.6 7.1 30 3.3 5.8 8.9 AK001024 0.16 0.11 4.6 2.0 9.8 2.6 7.6 14.1 AJ275355 0.15 0.08 4.6 17.3 5.4 9.2 5.1 5.5 U21931 0.48 0.14 4.6 4.3 2.6 2.1 8.4 9.6 X66403 0.17 0.19 4.4 9.0 10.9 9.3 5.1 6.7 X67734 0.25 0.09 4.3 6.8 3.1 5.8 7.9 8.4 U92981 0.20 0.23 4.3 3.2 4.8 5.6 5.4 6.3 X68879 0.05 0.08 4.3 2.0 12.3 2.7 5.6 4.7 AL137362 0.22 0.22 4.2 4.1 2.7 4.1 9.3 4.2 N _001756 0.28 0.13 4.1 10.6 3.9 2.7 10. 5.5 3 U80770 0.31 0.14 4.1 4.1 23.3 2.7 7.0 10.1 AL109792 0.16 0.19 4.0 4.5 4.3 8.8 8.7 3.9 X65962 0.33 0.05 3.8 25.3 5.7 5.1 19. 12.0 8 AK001856 0.40 0.21 3.8 7.0 2.6 3.1 2.9 7.8 AL022723 0.55 0.18 3.7 5.7 4.4 2.3 3.3 5.2 D38449 0.18 0.09 3.5 11.1 13.3 5.8 4.8 5.2 AL137489 0.74 0.26 3.3 2.9 2.6 3.3 2.5 5.4 AB000887 0.76 0.18 3.3 5.0 2.6 2.4 5.9 10.3 NM_012450 0.15 0.10 3.3 9.0 10.0 10.9 4.6 8.7 U86529 0.55 0.15 3.2 6.8 4.4 2.3 9.3 5.1 AK001244 0.79 0.31 3.2 5.5 2.3 2.3 3.9 2.8 AL133602 0.16 0.21 3.1 7.8 8.7 2.6 4.1 5.6 AB033080 0.31 0.31 3.1 4.6 3.0 3.5 2.2 4.2 AF023466 0.27 0.18 3.1 5.0 4.2 7.4 10. 3.8 1 AL117457 0.68 0.53 3.0 4.6 3.3 2.4 7.4 3.4 AC007059 0.37 035 3.0 5.7 3.1 2.4 2.6 2.4 ? 60179 0.34 0.21 2.9 3.5 2.3 3.1 8.0 4.7 M37238 0.60 0.36 2.9 2.0 3.2 2.1 2.9 4.6 L22569 0.32 0.12 2.9 2.1 6.2 3.0 13. 16.7 1 M80359 0.37 0.76 2.9 3.1 6.1 7.6 2.1 3.3 S70348 0.58 0.31 2.6 4.8 4.1 2.6 2.6 2.6 L13720 0.36 0.26 2.4 2.5 6.8 4.8 3.9 3.7 AL049423 0.33 0.30 2.4 3.7 3.8 2.8 2.9 3.4 AL050201 0.68 0.29 2.2 3.1 3.7 3.0 3.0 2.2 AF050078 0.87 0.33 2.1 8.4 2.5 2.2 2.6 4.4 A 0001753 0.53 0.28 2.1 5.0 2.2 2.8 3.6 4.6 X05323 0.39 0.13 2.1 7.8 2.6 2.4 21. 3.5 5 A 000266 0.61 0.30 2.0 2.4 4.8 3.4 4.9 3.9 Table 33: reduction by the peptide SEQ ID NO: 1 of the TNF-OI production induced by LPS from E. coli. in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 g / ml peptide .

The supernatant was collected and tested for TNF-OI levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Number of Gene cont Contr ID ID ID ID ID Access ID rol- ol- 19: 20: 21: 22: 23: 24: Cy3 Cy5 conconconconcontrol trol trol trol trol trol trol AF030555 0.10 0.39 8.7 2.2 11.3 9.9 3.0 2.1 AL050125 0.23 0.07 8.6 14.3 5.2 2.8 18. 8.3 7 AB011096 0.21 0.08 8.5 24.4 4.7 6.8 10. 7.5 4 J03068 0.54 0.21 8.3 2.4 2.2 4.1 3.0 6.0 M3390S 0.14 0.08 7.6 4.5 15.2 6.1 7.5 7.9 AJ272265 0.21 0.09 7.6 9.0 3.3 4.9 18. 14.5 8 J00210 0.41 0.07 7.2 15.0 2.8 3.1 11. 4.3 0 AK001952 0.42 0.21 6.9 4.9 2.5 3.1 7.6 4.5 X54131 0.09 0.20 6.4 6.5 7.7 15.0 5.6 4.1 AF064493 0.46 0.14 5.9 5.6 2.2 2.9 8.5 5.8 AL117567 0.44 0.22 5.8 3.3 2.9 2.3 5.7 14.9 L40933 0.16 0.03 5.6 11.0 4.8 3.5 8.5 76.3 M27190 0.19 0.28 5.3 3.0 3.8 3.6 5.8 3.6 AL031121 0.24 0.09 5.3 3.8 3.2 3.9 3.0 27.9 U27655 0.24 0.29 5.0 9.0 4.5 8.3 4.2 4.5 AB037786 0.12 0.03 4.7 54.1 2.8 2.3 2.2 11.0 X73113 0.29 0.13 4.7 6.5 6.0 2.4 6.7 6.3 AB010962 0.08 0.12 4.7 6.2 2.4 4.7 10. 4.2 9 AL096729 0.36 0.13 4.7 7.7 3.2 2.4 6.3 6.2 AB018320 0.16 0.18 4.6 7.1 30 3.3 5.8 8.9 AK001024 0.16 0.11 4.6 2.0 9.8 2.6 7.6 14.1 AJ275355 0.15 0.08 4.6 17.3 5.4 9.2 5.1 5.5 U21931 0.48 0.14 4.6 4.3 2.6 2.1 8.4 9.6 X66403 0.17 0.19 4.4 9.0 10.9 9.3 5.1 6.7 X67734 0.25 0.09 4.3 6.8 3.1 5.8 7.9 8.4 U92981 0.20 0.23 4.3 3.2 4.8 5.6 5.4 6.3 X68879 0.05 0.08 4.3 2.0 12.3 2.7 5.6 4.7 AL137362 0.22 0.22 4.2 4.1 2.7 4.1 9.3 4.2 M 001756 0.28 0.13 4.1 10.6 3.9 2.7 10. 5.5 3 U80770 0.31 0.14 4.1 4.1 23.3 2.7 7.0 10.1 AL109792 0.16 0.19 4.0 4.5 4.3 8.8 8.7 3.9 X65962 0.33 0.05 3.8 25.3 5.7 5.1 19. 12.0 8 AK001856 0.40 0.21 3.8 7.0 2.6 3.1 2.9 7.8 AL022723 0.55 0.18 3.7 5.7 4.4 2.3 3.3 5.2 D38449 0.18 0.09 3.5 11.1 13.3 5.8 4.8 5.2 AL137489 0.74 0.26 3.3 2.9 2.6 3.3 2.5 5.4 AB000887 0.76 0.18 3.3 5.0 2.6 2.4 5.9 10.3 NM_012450 0.15 0.10 3.3 9.0 10.0 10.9 4.6 8.7 U86529 0.55 0.15 3.2 6.8 4.4 2.3 9.3 5.1 AK001244 0.79 0.31 3.2 5.5 2.3 2.3 3.9 2.8 AL133602 0.16 0.21 3.1 7.8 8.7 2.6 4.1 5.6 AB033080 0.31 0.31 3.1 4.6 3.0 3.5 2.2 4.2 AF023466 0.27 0.18 3.1 5.0 4.2 7.4 10. 3.8 1 AL117457 0.68 0.53 3.0 4.6 3.3 2.4 7.4 3.4 AC007059 0.37 035 3.0 5.7 3.1 2.4 2.6 2.4 U60179 0.34 0.21 2.9 3.5 2.3 3.1 8.0 4.7 M37238 0.60 0.36 2.9 2.0 3.2 2.1 2.9 4.6 L22569 0.32 0.12 2.9 2.1 6.2 3.0 13. 16.7 1 M80359 0.37 0.76 2.9 3.1 6.1 7.6 2.1 3.3 S70348 0.58 0.31 2.6 4.8 4.1 2.6 2.6 2.6 L13720 0.36 0.26 2.4 2.5 6.8 4.8 3.9 3.7 AL049423 0.33 0.30 2.4 3.7 3.8 2.8 2.9 3.4 AL050201 0.68 0.29 2.2 3.1 3.7 3.0 3.0 2.2 AF050078 0.87 0.33 2.1 8.4 2.5 2.2 2.6 4.4 A 0001753 0.53 0.28 2.1 5.0 2.2 2.8 3.6 4.6 X05323 0.39 0.13 2.1 7.8 2.6 2.4 21. 3.5 5 AB014548 0.61 0.30 2.0 2.4 4.8 3.4 4.9 3.9 Table 34: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide. The supernatant was collected and tested for TNF-OI levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Generation number cont cont ID ID ID ID ID access ID rol- rol- 26: 27: 28: 29: 30: 31: Cy3 Cy5 conconconconcontrol trol trol trol trol trol trol trol U68018 0.13 0.71 11.2 2.2 8.0 2.3 6.7 25.6 NM_016015 0.92 1.59 2.3 2.3 3.5 3.7 3.4 22.9 AF071510 0.07 0.05 15.4 10.3 5.3 44.1 2.1 21.2 AC005154 0.17 1.13 2.7 7.2 12.6 6.4 3.3 20.6 M81933 0.13 0.21 4.3 3.1 3.2 4.3 5.6 18.2 AF124735 0.17 0.21 2.1 4.4 5.9 5.2 7.6 17.0 AL110125 0.30 0.08 5.0 2.7 6.8 10.2 2.8 12.0 NM_004732 0.15 0.16 7.6 4.0 3.4 2.2 2.9 11.4 AF030555 0.10 0.39 10.5 2.2 6.4 3.0 5.1 10.7 AF000237 1.80 2.37 3.4 2.5 2.4 2.1 3.7 9.9 AL031588 0.40 0.26 5.8 20.2 2.8 4.7 5.6 9.1 AL080077 0.15 0.21 2.4 2.0 11.9 3.8 2.3 8.7 NM_01436 0.90 2.52 2.4 4.3 2.4 2.6 3.0 8.6 AB002359 0.81 2.12 3.2 2.7 5.5 2.5 2.8 6.9 U33547 0.14 0.16 2.5 5.3 4.5 5.0 3.1 6.6 AL133051 0.09 0.07 7.7 6.3 5.4 23.1 5.4 6.5 AK000576 0.27 0.06 7.1 9.3 5.0 6.9 2.9 6.2 AF042378 0.36 0.39 3.3 3.0 9.5 4.5 3.4 6.2 AF093265 0.67 0.53 2.7 13.3 6.5 5.0 2.9 6.2 D80000 1.01 1.56 3.6 2.5 4.9 3.2 6.3 6.1 AF035309 3.61 4.71 2.7 6.6 5.2 4.9 2.7 6.0 M34175 4.57 5.13 3.2 3.1 4.0 4.6 2.7 6.0 AB020659 0.18 0.37 4.1 7.6 5.7 4.8 2.5 5.7 NM__004862 2.61 3.36 3.8 4.8 4.1 4.9 3.2 5.6 U00115 0.51 0.07 18.9 2.2 3.5 7.2 21.2 5.6 AF088868 0.45 0.20 4.7 10.0 3.2 6.4 6.0 5.6 AK001890 0.42 0.55 2.4 3.5 3.6 2.3 2.2 5.6 AL137268 0.49 0.34 3.8 2.3 5.0 3.5 3.3 5.4 X63563 1.25 1.68 2.5 8.1 3.4 4.8 5.2 5.4 D12676 0.35 0.39 2.9 3.4 2.6 2.2 3.5 5.3 AK000161 1.06 0.55 3.4 8.7 2.1 6.7 2.9 5.1 AF052138 0.64 0.51 2.9 2.8 2.7 5.2 3.6 5.0 AL096803 0.36 0.03 20.1 18.3 3.7 19.3 16.1 4.9 S49953 0.70 0.15 3.7 4.0 2.1 6.6 4.0 4.8 X89399 0.25 0.10 8.5 14.9 4.8 18.6 4.3 4.8 AJ005273 0.70 0.10 7.6 11.1 2.8 9.9 12.0 4.6 AK001154 1.70 0.96 2.4 4.4 2.9 8.9 2.4 4.5 AL133605 0.26 0.15 12.4 4.2 4.4 3.3 3.3 4.1 U71092 0.53 0.06 19.0 9.1 2.2 12.0 3.3 4.1 AF074723 0.67 0.54 4.0 3.2 3.1 3.4 6.0 4.0 AL137577 0.32 0.12 31.4 6.2 5.3 10.1 25.3 3.9 AF151043 0.48 0.35 2.6 2.2 2.0 3.3 2.2 3.8 AF131831 0.67 0.81 2.1 7.0 3.5 3.2 3.9 3.7 D50405 1.52 2.62 3.1 7.2 2.9 4.1 2.8 3.7 U78305 1.21 0.20 4.7 13.0 3.5 5.9 4.2 3.7 AL035562 0.24 0.01 30.2 81.9 5.6 82.3 6.2 3.7 U67156 1.15 0.30 6.6 3.0 2.2 2.3 2.5 3.6 AL031121 0.24 0.09 5.2 3.7 2.3 6.5 9.1 3.6 U13666 0.34 0.14 3.8 5.4 3.1 3.3 2.8 3.6 AB018285 0.53 0.13 14.9 13.9 5.9 18.5 15.2 3.5 D42053 0.63 0.40 2.3 7.1 5.6 9.2 2.6 3.5 AK001135 0.29 0.53 5.7 4.5 3.4 2.6 11.3 3.4 AL137461 0.25 0.02 23.8 9.0 2.7 59.2 12.5 3.3 N _006963 0.10 0.08 3.2 7.6 3.7 7.9 11.2 3.2 AL137540 0.67 0.79 3.9 2.6 5.6 4.2 3.5 3.1 AL137718 0.95 0.18 4.7 8.0 4.0 13.3 3.0 3.1 AF12086 1.20 0.59 4.6 4.0 2.0 4.6 3.6 3.1 S57296 0.59 0.17 7.3 12.1 2.3 20.0 22.2 3.0 NM_013329 0.16 0.08 6.9 14.3 9.7 3.3 7.2 3.0 AF038664 0.15 0.03 13.4 22.2 5.4 15.8 17.6 3.0 AF080579 0.34 1.03 3.3 3.0 6.7 2.1 2.9 2.9 AK001075 0.67 0.10 2.1 2.6 2.6 8.9 2.2 2.9 AB011124 0.46 0.04 9.6 72.0 6.0 33.9 13.6 2.9 J03068 0.54 0.21 2.2 5.0 2.4 5.2 3.6 2.8 D87120 0.87 0.87 2.2 2.0 4.7 2.3 2.0 2.8 AB006537 0.17 0.07 2.9 7.0 14.5 5.3 6.6 2.8 L34587 2.49 1.23 2.2 16.3 5.0 15.8 5.5 2.7 D31981 1.02 0.29 3.9 6.0 4.3 4.9 6.6 2.7 D00760 4.97 4.94 4.1 2.6 2.0 2.8 2.7 2.7 AC004774 0.25 0.12 2.3 6.3 3.8 5.2 5.2 2.6 AL024493 1.46 0.54 4.8 13.5 2.1 11.6 6.8 2.6 AB014536 1.80 1.29 3.2 9.5 3.8 6.8 2.6 2.6 X59770 0.59 0.16 9.6 4.7 3.9 3.2 4.9 2.5 AF052183 0.65 0.76 4.0 3.7 2.3 5.0 3.0 2.5 AK000541 0.92 0.27 4.5 13.9 3.6 18.1 4.3 2.5 U88528 1.37 0.86 3.1 5.4 2.1 2.8 2.1 2.4 97925 0.33 0.07 4.6 35.9 2.0 7.8 6.5 2.4 NM_013393 1.38 0.94 3.1 5.8 2.1 4.2 2.6 2.3 X62744 0.86 0.32 4.0 4.7 2.3 2.9 6.1 2.3 AF251040 0.64 0.30 6.7 3.4 2.9 3.9 5.7 2.2 AK000227 1.49 0.43 3.4 7.1 2.3 3.3 9.1 2.1 U88666 1.78 0.37 3.4 59 2.6 8.4 6.1 2.0 Table 35: reduction by the peptide SEQ ID NO: 1 of the TNF-CÍ production induced by LPS of E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml peptide . The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Generation number cont cont ID ID ID ID ID access ID rol- rol- 33: 34: 35: 36: 37: 38: Cy3 Cy5 conconconconcontrol trol trol trol trol trol trol trol AL049689 0.25 0.05 2.7 26.5 3.3 21.7 5.4 37.9 A 000576 0.27 0.06 3.0 19.1 3.9 23.0 3.1 28.3 X74837 0.10 0.07 5.6 10.0 10.8 12.3 12.0 19.9 AK000258 0.27 0.07 14.0 11.1 7.9 16.1 6.2 18.9 X89067 0.20 0.14 3.7 2.2 2.4 2.6 8.0 18.1 AL137619 0.16 0.08 6.3 6.7 10.8 10.5 7.09 16.5 NM_003445 0.17 0.07 4.0 23.6 2.9 13.6 4.3 14.4 X03084 0.36 0.15 2.4 3.1 2.9 7.7 3.4 13.7 U27330 0.39 0.08 2.4 2.5 2.6 12.1 3.5 13.0 AF070549 0.16 0.09 2.7 4.7 7.9 10.3 4.2 12.6 AB020335 0.19 0.24 2.9 2.6 2.0 7.3 4.7 12.4 M26901 0.09 0.12 14.9 2.2 7.3 12.0 20.8 12.0 Y07828 0.09 0.06 9.0 26.6 8.9 16.0 3.6 11.6 AK0001848 0.21 0.07 6.2 8.2 2.7 5.2 5.5 10.9 NM_016331 0.16 0.08 7.6 5.1 7.0 25.5 5.5 10.9 U75330 0.42 0.08 2.5 3.6 2.0 5.8 6.2 9.9 AB037826 0.16 0.11 3.8 6.0 3.4 13.4 6.0 9.8 M34041 0.30 0.13 4.5 4.5 3.7 8.6 5.6 9.8 D38449 0.18 0.09 2.3 25.8 11.7 2.3 3.2 9.5 AJ250562 0.13 0.10 10.0 8.4 2.2 8.1 16.3 9.1 A 001807 0.18 0.12 4.2 5.3 4.6 3.2 4.0 8.3 AL133051 0.09 0.07 5.1 13.6 6.0 9.1 2.2 8.2 Ü43843 0.61 0.10 2.0 6.4 2.3 16.1 2.2 8.1 NM_013227 0.28 0.15 7.5 3.1 2.5 6.9 8.5 7.8 AF226728 0.23 0.17 7.0 3.6 3.1 5.5 3.5 7.7 AK001024 0.16 0.11 3.9 12.3 2.7 7.4 3.3 7.0 AC002302 0.13 0.14 16.1 5.8 5.8 2.6 9.6 6.2 AB007958 0.17 0.27 2.0 2.3 11.3 3.3 3.0 6.1 AF059293 0.19 0.22 3.6 2.5 10.2 3.8 2.7 5.9 V01512 0.27 0.21 6.7 3.7 13.7 9.3 3.7 5.4 Ü82762 0.23 0.15 3.2 6.5 2.7 9.2 5.7 5.4 U44059 0.05 0.13 22.9 7.1 12.5 7.4 9.7 5.4 X05323 0.39 0.13 4.3 2.5 2.2 7.4 2.8 5.1 U72671 0.25 0.14 5.3 2.7 3.7 10.0 3.2 4.8 AL133626 0.26 0.25 2.2 4.2 2.9 3.0 2.6 4.7 X96401 0.31 0.29 6.9 2.3 4.9 3.1 2.9 4.6 AL117533 0.05 0.26 8.2 2.7 11.1 2.5 11.9 4.5 AK001550 0.10 0.30 8.0 2.0 4.9 2.1 7.8 4.5 AB032436 0.14 0.21 5.1 2.2 9.1 4.5 6.4 4.4 AL035447 0.28 0.23 4.3 3.7 8.7 5.2 3.7 4.2 U09414 0.28 0.25 4.0 2.2 4.7 3.3 7.2 4.2 AK001256 0.09 0.08 5.3 6.5 31.1 12.4 6.4 4.1 L14813 0.64 0.21 2.7 6.2 3.1 2.1 3.4 3.9 AF038181 0.06 0.18 '34.1 6.4 4.5 8.7 11.3 3.9 NM_001486 0.21 0.08 3.0 2.2 6.5 12.4 5.7 3.9 AB033000 0.24 0.22 3.4 3.3 7.1 5.5 4.5 3.8 AL117567 0.44 0.22 2.2 2.7 3.9 4.0 4.5 3.7 NM_012126 0.31 0.20 5.5 5.4 3.8 5.5 2.6 3.5 AL031687 0.16 0.27 5.9 2.6 3.4 2.3 4.9 3.5 X04506 0.29 0.32 5.4 4.4 6.9 5.5 2.1 3.5 N _006641 0.35 0.11 3.3 3.3 2.2 16.5 2.3 3.5 Y00970 0.12 0.14 8.2 8.8 3.1 6.2 17.5 3.4 X67098 0.19 0.26 2.4 3.1 7.8 3.5 4.4 3.3 U51990 0.56 0.19 2.2 3.0 2.8 13.7 2.9 3.0 AF030555 0.10 0.39 3.5 6.9 13.3 4.4 7.5 2.9 AL009183 0.46 0.19 6.0 4.1 2.8 8.6 2.6 2.8 AF045941 0.16 0.21 11.6 2.4 2.8 2.2 4.1 2.8 AF072756 0.33 0.07 2.5 5.3 3.9 32.7 2.3 2.7 X78678 0.10 0.20 18.0 3.5 4.1 2.5 14.6 2.6 AL031734 0.03 0.39 43.7 2.3 14.7 4.0 10.8 2.5 D87717 0.35 0.42 4.2 2.3 3.6 2.6 2.9 2.5 U01824 0.42 0.29 4.8 2.3 4.2 7.1 4.2 2.4 AF055899 0.14 0.31 9.5 12.3 7.4 4.7 6.6 2.3 U22526 0.09 0.45 4.1 3.4 10.4 2.2 17.9 2.3 AB032963 0.19 0.34 6.3 6.1 2.9 2.1 5.7 2.2 NM_015974 0.17 0.25 11.4 2.8 5.9 2.4 5.8 2..2 X82200 0.23 0.15 8.2 3.4 3.0 2.8 11.3 2.2 AL137522 0.12 0.26 12.1 3.7 12.6 6.9 4.3 2.2 Z99916 0.28 0.65 2.5 2.1 3.6 2.2 2.6 2.1 AF233442 0.41 0.31 2.6 3.6 3.6 4.5 3.4 2.1 AK001927 0.24 0.52 7.6 5.6 5.0 2.5 4.1 2.0 Table 36: Reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coll LPS in murine bone marrow macrophages Bone marrow-derived macrophages of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide. The supernatant was collected and tested for TNF- levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Number of Gen contr contr ID ID ID ID access ID ol- ol- 40: 42: 43: 44: 45: Cy3 Cy5 conconconcontrol control trol trol trol AF025840 0.34 0.96 3.4 2.0 2.0 2.1 4.3 AF132495 0.83 0.67 3.0 2.2 2.6 2.8 5.1 AL137682 0.73 0.40 2.0 5.3 4.8 2.9 8.2 U70426 0.23 0.25 3.1 3.0 5.3 3.1 12.2 AK001135 0.29 0.53 3.2 2.6 3.3 14.4 5.2 AB023155 0.47 0.21 2.7 4.8 8.1 4.2 10.4 AB033080 0.31 0.31 4.4 2.2 5.9 4.3 6.9 AF061836 0.29 0.31 3.2 2.5 11.1 18.8 6.8 AK000298 0.48 0.27 3.3 2.2 7.1 5.6 7.7 L75847 0.35 0.52 3.2 3.0 4.0 3.0 3.9 X97267 0.19 0.24 4.1 9.3 2.4 4.2 8.3 Z11933 0.09 0.23 8.7 2.5 3.6 4.3 8.2 AB037744 0.37 0.57 2.6 2.9 2.7 3.0 3.1 U90908 0.12 0.16 11.8 7.7 3.4 7.8 11.2 AL050139 0.29 0.60 5.2 2.4 3.3 3.0 2.8 AB014615 0.19 0.07 5.4 3.5 8.5 3.2 22.7 M28825 0.51 0.36 4.1 2.6 2.0 4.6 4.4 U27330 0.39 0.08 3.3 2.1 24.5 8.2 19.3 NM_006963 0.10 0.08 10.4 12.6 12.3 29.2 20.5 AF093670 0.44 0.53 4.0 2.6 2.6 4.3 2.9 A 000191 0.50 0.18 2.3 3.6 4.4 2.2 8.2 AB022847 0.39 0.24 2.1 6.9 4.5 2.8 6.2 AK000358 0.28 0.28 5.7 2.0 3.5 5.2 5.2 X74837 0.10 0.07 13.1 18.4 23.6 16.3 20.8 AF053712 0.17 0.08 11.3 9.3 13.4 10.6 16.6 AL133114 0.11 0.32 8.5 3.4 4.9 5.3 4.3 AF049703 0.22 0.24 5.1 6.0 3.3 2.7 5.4 AL137471 0.29 0.05 4.0 15.0 10.1 2.7 25.3 AL035397 0.33 0.14 2.3 2.8 10.6 4.6 9.3 AL035447 0.28 0.23 3.8 6.8 2.7 3.0 5.7 X55740 0.41 0.61 2.1 3.3 2.9 3.2 2.1 NM_004909 0.20 0.22 3.9 2.9 6.5 3.2 5.6 AF233442 0.41 0.31 2.9 4.7 2.7 3.5 3.9 U92980 0.83 0.38 4.2 4.1 4.8 2.3 3.1 AF105424 0.30 0.22 2.8 3.3 4.4 2.3 5.3 M26665 0.29 0.26 7.9 3.5 4.6 3.5 4.5 AF083898 0.20 0.34 18.7 3.8 2.2 3.6 3.5 AJ009771 0.33 0.06 2.3 17.6 15.9 2.5 20.3 AL022393 0.05 0.33 32.9 2.4 3.0 69.4 3.4 AF039400 0.11 0.19 8.4 2.9 5.1 18.1 5.9 AJ012008 0.42 0.43 5.1 3.3 3.2 6.2 2.6 AK000542 0.61 0.24 2.1 4.5 5.0 3.7 4.4 AL133654 0.27 0.40 2.8 2.1 2.5 2.5 2.6 AL137513 0.43 0.43 6.4 3.2 3.8 2.3 2.3 U05227 0.38 0.36 5.0 3.1 3.1 2.2 2.8 D38449 0.18 0.09 5.8 6.7 6.7 9.1 10.4 U80770 0.31 0.14 3.9 3.8 6.6 3.1 6.8 X61177 0.40 0.27 2.6 4.4 9.8 8.1 3.6 U35246 0.15 0.42 5.8 2.8 2.6 4.5 2.2 AB17016 0.27 0.29 6.0 2.6 3.4 3.1 3.1 X82153 0.45 0.20 4.2 5.2 4.8 4.4 4.6 AC005162 0.12 0.28 11.9 3.4 6.8 18.7 3.2 AL137502 0.22 0.16 3.9 4.9 7.3 3.9 5.3 U66669 0.30 0.40 10.3 3.5 5.2 2.3 2.1 AK000102 0.39 0.30 2.8 5.3 5.2 4.1 2.8 AF034970 0.28 0.05 3.3 8.5 15.7 4.0 17.3 AK000534 0.13 0.29 6.8 2.3 4.0 20.6 2.9 J04599 0.39 0.30 4.0 3.7 4.0 4.8 2.8 AL133612 0.62 0.33 2.7 3.4 5.2 3.0 2.5 D10495 0.18 0.10 12.0 20.7 8.7 6.8 8.1 X58467 0.07 0.24 15.4 4.7 7.9 34.4 3.4 AF131806 0.31 0.25 2.06 3.4 5.7 7.0 3.2 ?? 000351 0.34 0.13 4.0 6.9 5.5 2.8 6.3 AF075050 0.55 0.09 2.7 17.8 5.1 2.2 8.3 AK000566 0.15 0.35 6.7 2.2 6.8 6.4 2.1 U43328 0.44 0.19 2.5 6.2 6.9 7.8 3.8 AF045941 0.16 0.21 6.8 7.5 4.8 6.9 3.4 U27655 0.24 0.29 5.5 4.9 2.9 4.9 2.4 AK000058 0.25 0.15 5.0 9.7 16.4 2.7 4.5 AL035364 0.32 0.26 4.4 4.2 7.3 2.8 2.6 AK001864 0.40 0.25 3.7 3.7 4.6 3.2 2.6 AB015349 0.14 0.24 10.5 2.8 3.7 8.0 2.7 V00522 0.62 0.22 4.8 3.9 4.7 2.5 3.0 U75330 0.42 0.08 2.1 9.6 13.2 3.3 7.8 N _007199 0.15 0.25 8.7 7.8 8.6 16.1 2.5 D30742 0.28 0.09 6.2 38.7 7.4 2.4 6.8 X05978 0.63 0.17 2.7 4.8 9.4 2.2 3.6 AF240467 0.11 0.10 13.8 13.3 4.7 7.7 4.9 Table 37: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide. The supernatant was collected and tested for TNF-OI levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 + 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 + 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Number of with ID ID ID ID ID ID ID ID access access trolley 53: 54: 47: 48: 49: 50: 51: 52: Cy3 1- conconconconconconCy5 trol trol trol trol trol trol trol trol D00115 0.51 0.07 27.4 7.3 2.4 3.1 4.8 8.3 3.5 20.0 M91036 0.22 0.02 39.1 32.5 5.2 2.2 37.0 6.0 16.2 18.0 AK000070 0.36 0.18 3.8 7.6 2.6 15.1 12.2 9.9 17.2 15.3 AF055899 0.14 0.31 6.7 3.7 9.7 10.0 2.2 16.7 5.4 14.8 AK001490 0.05 0.02 14.1 35.8 3.2 28.6 25.0 20.2 56.5 14.1 X97674 0.28 0.28 3.2 3.7 4.0 10.7 3.3 3.1 4.0 13.2 AB022847 0.39 0.24 4.1 4.4 4.5 2.7 3.7 10.4 5.0 11.3 AJ275986 0.26 0.35 5.8 2.3 5.7 2.2 2.5 9.7 4.3 11.1 D104495 0.18 0.10 8.0 3.4 4.6 2.0 6.9 2.5 12.7 10.3 L36642 0.26 0.06 5.8 14.2 2.6 4.1 8.9 3.4 6.5 6.6 M31166 0.31 0.12 4.8 3.8 12.0 3.6 9.8 2.4 8.8 6.4 AF176012 0.45 0.26 3.1 2.9 2.8 2.6 2.3 6.9 3.0 5.8 AF072756 0.33 0.07 9.9 9.3 4.4 4.3 3.2 4.9 11.9 5.4 NM 014439 0.47 0.07 12.0 7.1 3.3 3.3 4.7 5.9 5.0 5.4 AJ271351 0.46 0.12 3.4 3.5 2.3 4.7 2.3 2.7 6.9 5.2 AK000576 0.27 0.06 7.4 15.7 2.9 4.7 9.0 2.4 8.2 5.1 AJ272265 0.21 0.09 6.2 7.9 2.3 3.7 10.3 4.5 4.6 4.7 AL122038 0.46 0.06 6.7 4.5 2.6 4.3 16.4 6.5 26.6 4.6 AK000307 0.23 0.09 3.7 4.0 4.3 3.2 5.3 2.9 13.1 4.4 AB029001 0.52 0.21 14.4 4.3 4.6 4.4 4.8 21.9 3.2 4.2 A62437 0.38 0.13 12.6 6.5 4.2 6.7 2.2 3.7 4.8 3.9 AF0648554 0.15 0.16 2.6 2.9 6.2 8.9 14.4 5.0 9.1 3.9 AL031588 0.40 0.26 8.3 5.2 2.8 3.3 5.3 9.0 5.6 3.4 X89399 0.25 0.10 15.8 12.8 7.4 4.2 16.7 6.9 12.7 3.3 D45399 0.21 0.18 3.0 4.7 3.3 4.4 8.7 5.3 5.1 3.3 AB037716 0.35 0.40 5.1 7.5 2.6 2.1 3.5 3.1 2.4 2.8 X79981 0.34 0.10 4.7 7.2 3.2 4.6 6.5 51 5.8 2.7 AF034208 0.45 0.24 2.7 10.9 2.1 3.7 2.3 5.9 2.2 2.5 AL133355 0.22 0.23 2.3 3.4 7.3 2.7 3.3 4.3 2.8 2.5 NM_016281 0.40 0.19 6.6 10.6 2.1 2.8 5.0 11.2 10.6 2.5 AF023614 0.11 0.42 2.2 2.2 6.0 7.5 5.0 2.7 2.0 2.4 AF056717 0.43 0.62 4.3 3.2 5.1 4.0 4.6 9.7 3.1 2.2 AB029039 0.79 0.49 2.7 3.3 3.7 2.0 2.3 2.4 4.8 2.2 J03634 0.40 0.12 3.7 2.3 2.3 4.0 10.5 4.1 9.1 2.2 U80764 0.31 0.18 2.3 7.4 4.2 2.3 5.1 3.3 8.8 2.1 AB032963 0.19 0.34 4.0 7.3 5.0 3.0 2.9 6.7 3.8 2.1 X82835 0.25 0.38 2.0 2.7 2.9 7.7 3.3 3.1 3.5 2.0 Table 36: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages of murine bone marrow-derived macrophages of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 g / ml of the peptide.

The supernatant was collected and tested for TNF-OI levels by ELISA. The data represent the amount of TNF-cx resulting from duplicated cavities of macrophages derived from bone marrow incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours. Example 5 Determination of Toxicity of Cationic Peptides The potential toxicity of the peptides was measured in two ways. First, the assay of cytotoxicity detection kit (Roche) (lactate dehydrogenase-LDH) was used. It is a colorimetric assay for the quantification of cell death and cell lysis, based on the measurement of LDH activity released from the cytosol of damaged cells into the supernatant. The LDH enzyme is a stable cytoplasmic enzyme present in all cells and is released to the cell culture supernatant when damage to the plasma membrane occurs. An increase in the amount of dead or damaged cells in the plasma membrane results in an increase in the activity of the LDH enzyme in the culture supernatant, as measured with an ELISA slide reader, OD490nm (the amount of color formed in the assay is proportional to the number of cells used). In this assay, human bronchial epithelial cells (16HBEol4, HBE) were incubated with 100 μl of peptide for 24 hours, the supernatant was removed and tested for LDH. The other assay used to measure the toxicity of the cationic peptides is the WST-1 assay (Roche). This assay is a colorimetric assay for the quantification of cell proliferation and cell viability, based on the cutting of the tetrazolium salt WST-1 by mitochondrial dehydrogenases in viable cells (a non-radioactive alternative to the assay of incorporation of [¾] -thymidine). In this assay, the HBE cells were incubated with 100 iq of the peptide for 24 hours, and then 10 μ? / Cavity of the cell proliferation reagent WST-1 was added. The cells were incubated with the reagent and the plate is then measured with an ELISA plate reader, OD490nm. The results shown below in Tables 16 and 17 show that most of the peptides are not toxic to the cells tested. However, four of the peptides of formula F (SEQ ID NOS: 40, 41, 42 and 43) did not induce membrane damage, as measured by both assays. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the tumor necrosis oi factor (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains non-methylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NF B). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Likewise, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking ot-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and memory T cells through interaction with CCR6. Table 38: reduction by the peptide SEQ ID NO: 1 of the TNF-α production induced by LPS of E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml peptide . The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 ± 0.09 ng / ml) or 24 hours (1.7 ± 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Table 39: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by LPS from E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 g / ml peptide . The supernatant was collected and tested for TNF-a levels by ELISA. The data represent the amount of TNF-a resulting from duplicate cavities of bone marrow-derived macrophages incubated with LPS alone for 6 hours (1.1 + 0.09 ng / ml) or 24 hours (1.7 + 0.2 ng / ml). Background levels of TNF-a were 0.038 ± 0.008 ng / ml for 6 hours and 0.06 ± 0.012 ng / ml for 24 hours.

Table 40: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide.

Peptide (10 pg / ml) IL-8 (ng / ml) No peptide 0.164 LPS, no peptide 0.26 SEQ ID 1 0.278 SEQ ID 6 0.181 SEQ ID 7 0.161 SEQ ID 9 0.21 SEQ ID 10 0.297 SEQ ID 13 0.293 SEQ ID 14 0.148 SEQ ID 16 0.236 SEQ ID 17 0.15 SEQ ID 19 0.161 SEQ ID 20 0.151 SEQ ID 21 0.275 SEQ ID 22 0.314 SEQ ID 23 0.284 SEQ ID 24 0.139 SEQ ID 26 0.201 SEQ ID 27 0.346 SEQ ID 28 0.192 SEQ ID 29 0.188 SEQ ID 30 0.284 SEQ ID 31 0.168 SEQ ID 33 0.328 SEQ ID 34 0.315 SEQ ID 35 0.301 SEQ ID 36 0.166 SEQ ID 37 0.269 SEQ ID 38 0.171 SEQ ID 40 0.478 SEQ ID 41 0.371 SEQ ID 42 0.422 SEQ ID 43 0.552 SEQ ID 44 0.265 SEQ ID 45 0.266 SEQ ID 47 0.383 SEQ ID 48 0.262 SEQ ID 49 0.301 SEQ ID 50 0.141 SEQ ID 51 0.255 SEQ ID 52 0.207 SEQ ID 53 0.377 SEQ ID 54 0.133 Table 41: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli Olll: B4 LPS in the presence or absence of 20 g / ml of the peptide.

Table 42: reduction by the peptide SEQ ID NO: 1 of the TNF-α production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide.

SEQ ID NO: 2 (yg / ml) IL-8 (pg / ml) 0 552 ± 90 0.1 670 ± 155 1 712 + 205 10 941 + 15 50 1490 + 715 Table 43: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 and g / rtil of the peptide.

Table 44: reduction by peptide SEQ ID NO: 1 of TNF-ct production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide.

Condition MCP-1 (pg / ml) TNF-OI (pg / ml) Water 16.5 + 5 664 ± 107 Peptide 111 ± 30 734 ± 210 6.5 ± 0.5 393 + 129 Table 45: reduction by the peptide SEQ ID NO: 1 of The production of TNF-OI induced by LPS from E. coll in bone marrow macrophages of murine bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml of E.coli Olll: B4 LPS in the presence or absence of 20 pg / ml of the peptide.

Treatment Peptide TNF-OI (pg / ml) 56 ± 8 LPS treatment, no 15201 ± 186 peptide SEQ ID 1 274 ± 15 SEQ ID 5 223 ± 45 SEQ ID 6 297 ± 32 SEQ ID 7 270 ± 42 SEQ ID 8 166 ± 23 SEQ ID 9 171 + 33 SEQ ID 10 288 ± 30 SEQ ID 12 299 ± 65 SEQ ID 13 216 + 42 SEQ ID 14 226 ± 41 SEQ ID 15 346 ± 41 SEQ ID 16 341 ± 68 SEQ ID 17 249 ± 49 SEQ ID 19 397 ± 86 SEQ ID 20 285 ± 56 SEQ ID 21 263 ± 8 SEQ ID 22 195 ± 42 SEQ ID 23 254 ± 58 SEQ ID 24 231 + 32 SEQ ID 26 281 ± 34 SEQ ID 27 203 ± 42 SEQ ID 28 192 ± 26 SEQ ID 29 242 ± 40 SEQ ID 31 307 ± 71 SEQ ID 33 196 ± 42 SEQ ID 34 204 ± 51 SEQ ID 35 274 ± 76 SEQ ID 37 323 ± 41 SEQ ID 38 199 + 38 SEQ ID 43 947 ± 197 SEQ ID 44 441 + 145 SEQ ID 45 398 + 90 SEQ ID 48 253 ± 33 SEQ ID 49 324 ± 38 SEQ ID 50 311 ± 144 SEQ ID 53 263 + 40 SEQ ID 54 346 ± 86 Table 41: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages from murine bone marrow derived acrophages from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. colx 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide. Example 6 Determination of Toxicity of Cationic Peptides The potential toxicity of the peptides was measured in two ways. First, the assay of cytotoxicity detection kit (Roche) (lactate dehydrogenase-LDH) was used. It is a colorimetric assay for the quantification of cell death and cell lysis, based on the measurement of LDH activity released from the cytosol of damaged cells into the supernatant. The LDH enzyme is a stable cytoplasmic enzyme present in all cells and is released to the cell culture supernatant when damage to the plasma membrane occurs. An increase in the amount of dead or damaged cells in the plasma membrane results in an increase in the activity of the LDH enzyme in the culture supernatant, as measured with an ELISA slide reader, OD490nm (the amount of color formed in the assay is proportional to the number of cells used). The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which tumor factor OI (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. I cooked It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains non-methylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, R.E.W., and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Also, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and memory T cells through interaction with CCR6. Table 46: reduction by the SEQ ID NO: 1 peptide of the α-LPS-induced TNF-α production. coli in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of peptide.

Example 7 Determination of Toxicity of Cationic Peptides The potential toxicity of the peptides was measured in two ways. First, the assay of cytotoxicity detection kit (Roche) (lactate dehydrogenase-LDH) was used. It is a colorimetric assay for the quantification of cell death and cell lysis, based on the measurement of LDH activity released from the cytosol of damaged cells into the supernatant. The LDH enzyme is a stable cytoplasmic enzyme present in all cells and is released to the cell culture supernatant when damage to the plasma membrane occurs. An increase in the amount of dead or damaged cells in the plasma membrane results in an increase in the activity of the LDH enzyme in the culture supernatant, as measured with an ELISA slide reader, OD490nm (the amount of color formed in the assay is proportional to the number of cells used) -. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the tumor necrosis factor (TNF-) is of extreme importance. TNF-OI and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains non-methylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E. ., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Likewise, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of -defensin, HNP-1 and HNP-2, have been indicated for having direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for cells immature dendrites and T cells of memory through interaction with CCR6. Table 47: reduction by peptide SEQ ID NO: 1 of T F-OI production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 g / ml of the peptide.

Phosphorylated MAP kinase cell line p38 ERKl / 2 RA 264.7 SEQ ID NO: 3 - + SEQ ID NO: 2 + + HBE SEQ ID NO: 3 + SEQ ID NO: 2 + + THP-1 SEQ ID NO: 3 + + SEQ ID NO: 2 Table 48: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in murine bone marrow macrophages Bone marrow-derived macrophages of BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide.

Example 8 Determination of Toxicity of Cationic Peptides The potential toxicity of the peptides was measured in two ways. First, the cyto-toxicity detection kit assay was used (Roche) (lactate dehydrogenase-LDH). It is a colorimetric assay for the quantification of cell death and cell lysis, based on the measurement of LDH activity released from the cytosol of damaged cells into the supernatant. The enzyme LDH is a stable cytoplasmic enzyme present in all cells and is released into the supernatant of the cell culture when damage occurs to the plasma membrane. An increase in the amount of dead or damaged cells in the plasma membrane results in an increase in the activity of the LDH enzyme in the culture supernatant, as measured with an ELISA slide reader, OD490nm (the amount of color formed in the assay is proportional to the number of cells used). The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the tumor necrosis factor-a (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-a. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, R.E.W., and R. Lehrer, 1998.

Cationic peptides: a ne source of antibiotics. Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, REW, and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410 Hancock, RE, 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials, Lancet Infectious Diseases 1: 156-164), although it was not known if the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Also, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the syndrome of deficiency of specific gxánulos that lack completely of -defensinas, suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and T cells of memory through interaction with CCR6. Table 49: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide.

Table 50: Reduction by peptide SEQ ID NO: 1 of TNF-c¿ production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide.

Treatment Peptide Control 1.88 + 0.16 X 104 SEQ ID NO: 48 1.98 ± 0.18 X 104 SEQ ID NO: 26 7.1 ± 1.37 X 104 SEQ ID NO: 30 5.79 + 0.43 X 103 SEQ ID NO: 37 1.57 ± 0.44 X 104 SEQ ID NO: 5 2.75 + 0.59 X 104 SEQ ID NO: 7 5.4 ± 0.28 X 103 SEQ ID NO: 9 1.23 ± 0.87 X 104 SEQ ID NO: 14 2.11 + 0.23 X 103 SEQ ID NO: 20 2.78 ± 0.22 X 104 SEQ ID NO: 23 6.16 ± 0.32 X 104Table 51: reduction by the peptide SEQ ID NO: 1 of the TNF-α production induced by LPS of E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml E. coli Olll: B4 LPS in the presence or absence of 20 ug / ml of the peptide .

Treatment CFU / ML (blood) # of Mice that Survived (3 days) / Total mice in group No Peptide 7.6 ± 1.7 X 103 6/8 SEQ ID NO: 1 0 4/4 SEQ ID NO: 27 2.25 + 0.1 X 102 3/4 SEQ ID NO: 30 1.29 ± 0.04 X 102 4/4 SEQ ID NO: 37 9.65 ± 0.41 X 102 4/4 SEQ ID NO: 5 3.28 ± 1.7 X 103 4/4 SEQ ID NO: 6 1.98 ± 0.05 X 102 3/4 SEQ ID NO: 7 3.8 + 0.24 X 103 4/4 SEQ ID NO: 9 2.97 + 0.25 X 102 4/4 SEQ ID NO: 13 4.83 ± 0.92 X 103 3/4 SEQ ID NO: 17 9.6 ± 0.41 X 102 4/4 SEQ ID NO: 20 3.41 ± 1.6 X 103 4/4 SEQ ID NO: 23 4.39 ± 2.0 X 103 4/4 Table 52: reduction by the peptide SEQ ID NO: 1 of the production of TNF-a-induced LPS of E. coli in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured for either 6 or 24 hours with 100 ng / ml of E. coli Olll: B4 LPS in presence or absence of 20 pg / ml of the peptide.

Table 53: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide.

Table 54: reduction by peptide SEQ ID NO: 1 of TNF-a production induced by LPS from E. col! in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / mice were cultured for either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide.

Peptide MIC (G / ML) E. Coli S. aureus P. aejrug S. ryphim C. F od EHEC Polymyxin 0.25 16 0.25 0.5 0.25 0.5 Gentamicin 0.25 0.25 0.25 0.25 0.25 0.5 SEQ ID NO: 1 32 > 96 64 8 4 SEQ ID NO: 5 128 > > > 64 64 SEQ ID NO: 6 128 > > 128 64 64 SEQ ID NO: 7 > > > > > > SEQ ID NO: B > > > > > > SEQ ID NO: 9 > > > > > > SEQ ID NO: 10 > > > > > 24 SEQ ID NO: 12 > > > > > > SEQ ID NO: 13 > > > > > > SEQ ID NO: 14 > > > > > > I KNOW THAT ?? NO: 15 128 > > > 128 64 SEQ ID NO: 16 > > > > > > SEQ ID NO: 17 > > > > > > SEQ ID NO: 19 8 16 16 64 4 4 SEQ ID NO: 2 4 16 32 16 64 SEQ ID NO: 20 8 8 8 8 16 8 SEQ ID NO: 21 646 64 96 64 32 32 SEQ ID NO: 22 8 12 24 8 4 4 SEQ ID NO: 23 4 8 8 16 4 4 SEQ ID NO: 24 16 16 4 16 16 4 SEQ ID NO: 26 0.5 32 64 2 2 0.5 SEQ ID NO: 27 8 64 64 16 2 4 SEQ ID NO: 28 > > > 64 64 128 SEQ ID NO: 29 2 > > 16 32 4 SEQ ID NO: 30 16 > 128 16 16 4 SEQ ID NO: 31 > > 128 > > 64 SEQ ID NO: 33 16 32 > 16 64 8 SEQ ID NO: 34 8 > > 32 64 8 SEQ ID NO: 35 4 128 64 8 8 4 SEQ ID NO: 36 32 > > 32 32 16 SEQ ID NO: 37 > > > > > > SEQ ID NO: 38 0.5 32 64 4 8 4 SEQ ID NO: 40 4 32 8 4 4 2 SEQ ID NO: 41 4 64 8 8 2 2 SEQ ID NO: 42 1.5 64 4 2 2 1 SEQ ID NO: 43 8 128 16 16 8 4 SEQ ID NO: 44 8 > 128 128 64 64 SEQ ID NO: 45 8 > 128 128 16 16 SEQ ID NO: 47 4 > 16 16 4 4 SEQ ID NO: 48 16 > 128 16 1 2 SEQ ID NO: 49 4 > 16 8 4 4 SEQ ID NO: 50 8 > 16 16 16 8 SEQ ID NO: 51 4 > 8 32 4 8 SEQ ID NO: 52 8 > 32 8 2 2 SEQ ID NO: 53 4 > 8 8 16 8 SEQ ID NO: 54 64 > 16 64 16 32 Example 9 Anti-Sepsis / Anti-Inflammatory Activity Polynucleotide arrays were used to determine the effect of cationic peptides on the transcriptional response of epithelial cells. The human epithelial cell line A549 was maintained in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS), Medicorp). A549 cells were plated in 100 mm tissue culture dishes at 2.5 x 10 cells / dish, cultured overnight and then incubated with 100 ng / ml E. coli 0111: B4 LPS (Sigma), without (control) or with 50 ug / ml of peptide or medium only for 4 hours. After stimulation, the cells were washed once with buffered saline (PBS) with phosphate, treated with diethyl pyrocarbonate, and separated from the dish using a cell scraper. Total RNA was isolated using RNAqueous (Ambion, from Austin, Texas, United States). The RNA beads were re-suspended in RNase-free water containing Superase-In (RNase inhibitor); Ambion). DNA contamination was removed with the DNA-free kit from Ambion. RNA quality was determined by gel electrophoresis in 1% agarose gel. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery.

Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytogens of which the tumor necrosis factor (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The > Endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid. { VIA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-OI. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, RE, and G. Diamond, 2000. The role of cationic peptides in innate host defenses. Trends in Microbiology 8: 402- 410; Hancock, REW, 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials, Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Also, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking in -defensins, suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and T cells from memory through interaction with CCR6. The arrays of polynucleotides used were arrays of human operons (the identification number for the genome is PRHU04-S1), which consist of about 14,000 human oligos in duplicate. Probes were prepared from 10] iq of total RNA and marbed with dUTP marbed with Cy3 or Cy5. The probes were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Perkin Elmer array scanner. The image processing software (Imapolynucleo-tide 5.0, Marina Del Rey, California, United States) determines the average intensity of spots, average intensities, and background intensities. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS.

In Table 1, the peptide, SEQ ID NO: 27, is shown to potently reduce the expression of many of the polynucleotides up-regulated by E. coli 0111: B4 LPS, as studied by the micro-arrays of polynucleotides. Peptide (50 pg / ml) and LPS (0.1 ug / ml) or LPS were only incubated with A549 cells for 4 hours and the RNA was isolated. 5] ig of total RNA were used to make marseted cDNA probes Cy3 / Cy5 and hybridized in arrays of human operons (PRHU04). The intensity of the unstimulated cells is shown in the third column of Table 1. The column "ratio: LPS / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS divided by the intensity of the non-stimulated cells. stimulated. The column "Relationship: LPS + ID 27 / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS and peptide divided between unstimulated cells. Table 55: Reduction by peptide SEQ ID NO: 1 of T Fa production induced by LPS from E. coli in bone marrow macrophages of murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide.

Gen Control Number: Relationship: Access Magnitude Only LPS / Control of Medium D87451 715.8 183.7 AF061261 565.9 36.7 D17793 220.1 35.9 M14630 168.2 31.3 AL049975 145.6 62.3 L04510 139.9 213.6 U10991 101.7 170.3 U39067 61.0 15.9 X03342 52.6 10.5 NM_004850 48.1 11.8 AK000942 46.9 8.4 AB040057 42.1 44.3 AB020719 41.8 9.4 AB007856 41.2 15.7 J02783 36.1 14.1 AL13737S 32.5 17.3 AL137730 29.4 11.9 D25328 27.3 8.5 AF047470 25.2 8.2 M86752 22.9 5.9 M90696 19.6 6.8 AK00143 19.1 6.4 AF038406 17.7 71.5 AK000315 17.3 17.4 M54915 16.0 11.4 D29011 15.3 41.1 AK000237 15.1 9.4 AL034348 15.1 15.8 AL161991 14.2 8.1 A1049250 12.7 5.6 al050361 12.6 13.0 U74324 12.3 5.2 M22538 12.3 7.6 D87076 11.6 6.5 M 006327 11.5 10.0 AK001083 11.1 8.6 AJ001403 10.8 53.4 M64788 10.7 7.6 X06614 10.7 5.5 U85611 10.3 8.1 U23942 10.1 10.2 AL031983 9.7 302.8 NM_007171 9.5 6.5 AK000403 9.5 66.6 NM_002950 9.3 35.7 L05515 8.9 6.2 X83368 8.7 27.1 M30269 8.7 5.5 M91083 8.2 6.6 D29833 7.7 5.8 AB024536 7.6 8.0 U39400 7.4 7.3 AF028789 7.4 27.0 NM 003144 7.3 5.9 X52195 7.3 13.1 U43895 6.9 6.9 L25876 6.7 10.3 L04490 6.6 11.1 Z18948 6.3 11.0 D10522 6.1 5.8 NM_014442 6.1 7.6 081375 6.0 6.4 AF041410 5.9 5.3 U24077 5.8 14.4 AL137614 4.8 6.8 NM_002406 4.7 5.3 AB002348 4.7 7.6 AF165217 4.6 12.3 Z14093 4.6 5.4 U82671 3.8 44.5 AL050136 3.6 5.0 NM_005135 3.6 5.0 AK001961 3.6 5.9 AL034410 3.2 21.3 S74728 3.1 9.2 AL049714 3.0 19.5 N J314075 2.9 11.5 AF189279 2.8 37.8 J03925 2.7 9.9 N _012177 2.6 26.2 NM_004519 2.6 21.1 28825 2.6 16.8 X16940 2.4 11.8 X03066 2.2 36.5 AK001237 2.1 18.4 AB028971 2.0 9.4 AL137665 2.0 7.3 Table 56: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide.

Control Number: Relationship: Access Magnitude LPS Only / Control of the Medium NM_017433 167.8 0.03 X60848 36.2 0.04 X60483 36.9 0.05 AF151079 602.8 0.05 M96846 30.7 0.05 S79854 39.4 0.06 AB18266 15.7 0.08 M33374 107.8 0.09 AF005220 105.2 0.09 Z80783 20.5 0.10 Z46261 9.7 0.12 Z80780 35.3 0.12 U33931 18.9 0.13 M60750 35.8 0.14 Z83738 19.3 0.15 Y14690 7.5 0.15 M30938 11.3 0.16 L36055 182.5 0.16 Z80779 54.3 0.16 AF226869 7.1 0.18 D50924 91.0 0.18 AL133415 78.1 0.19 AL050179 41.6 0.19 AJ005579 5.4 0.19 808999 11.6 0.19 N _004873 6.2 0.19 X57138 58.3 0.20 AF081281 7.2 0.22 U96759 6.6 0.22 U85977 342.6 0.22 D13315 7.5 0.22 AC003007 218.2 0.22 AB032980 246.6 0.22 Ü40282 10.1 0.22 U81984 4.7 0.23 X91788 9.6 0.23 AF08081 6.9 0.24 L31881 13.6 0.24 X61123 5.3 0.24 L32976 6.3 0.24 M27749 5.5 0.24 X57128 9.0 0.25 X80907 5.8 0.25 Z34282 100.6 0.26 X00089 4.7 0.26 AL035252 4.6 0.26 X95289 27.5 0.26 AJ001340 4.0 0.26 NMJD1 161 10.6 0.27 U60873 6.4 0.27 X91247 84.4 0.27 AK001284 4.2 0.27 U90840 6.6 0.24 X53777 39.9 0.27 AL035067 10.0 0.28 AL117665 3.9 0.28 L14561 5.3 0.28 L19779 30.6 0.28 AL049782 285.3 0.28 X00734 39.7 0.29 A 001761 23.7 0.29 U72661 4.4 0.29 S48220 1,296.1 0.29 AF025304 4.5 0.30 S82198 4.1 0.30 Z80782 31.9 0.30 X68194 7.9 0.30 AB028869 4.2 0.30 AK000761 4.3 0.30 Table 57: reduction by peptide SEQ ID NO: 1 of FoI-induced production of LPS from E. coll in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coll 0111: B4 LPS in the presence or absence of 20 g / ml of the peptide.

Control Number: Relationship Relationship Protein Relationship InmensiLPS access: conLTA: conCpG: with / Polynucleoty Only trolley trol trol trolley of the medium 15131 20 82 80 55 IL-? ß M57422 20 77 64 90 sad-traprolin X53798 20 73 77 78 MIP-2a M35590 188 50 48 58 ??? ~ 1ß L28095 20 49 57 50 ICE M87039 20 37 38 45 iNOS X57413 20 34 40 28 TGBP X15842 20 20 21 15 X12531 489 19 20 26 MIP-IOÍ U14332 20 14 15 12 IL-15 M59378 580 10 13 11 TNFR1 U37522 151 6 6 6 TRAIL M57999 172 3.8 3.5 3.4 NF- B U36277 402 3.2 3.5 2.7? - ?? (alpha sub-unit) X76850 194 3 3.8 2.5 MAPKAP-2 U06924 858 2.4 3 3.2 Stat 1 X14951 592 2 2 2 CD18 X60671 543 1.9 2.4 2.8 NF-2 34510 5970 1.6 2 1.4 CD14 X51438 2702 1.3 2.2 2.0 Vimentin X68932 4455 0.5 0.7 0.5 c-Fms Z21848 352 0.5 0.6 0.6 DNA polymerase X70472 614 0.4 0.6 0.5 B-myb Table 58: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide.

Control Number: Relationship Relationship Protein Relationship InmensiLPS access: conLTA: conCpG: with / Polynucleoty Only trolley trol trol trol ol the medium X72307 20 1.0 23 1.0 L38847 20 1.0 21 1.0 L34169 393 0.3 3 0.5 J04113 289 1 4 3 Nur Z50013 20 7 21 5 X84311 20 4 12 2 Ciclin Al U95826 20 5 14 2 Ciclin G2 X87257 123 2 4 1 Elk-1 J05205 20 18 39 20 Jun-D J03226 20 11 19 14 Jun-B M83649 20 71 80 42 Fas 1 receiver 83312 20 69 91 57 CD40L receiver X52264 20 17 23 9 ICAM-1 M13945 573 2 3 2 Pim-1 U60530 193 2 3 3 Poor Related Pro tein D10329 570 2 3 2 CD7 X06381 20 55 59 102 X70296 20 6.9 13 22 U36340 20 38 7 7 CACCC S76657 20 11 6 7 CRE-BP1 Ü19119 272 10 4 4 Table 59: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide.

Product Untreated LPS LTA Cpg CD14a 1.0 2.2 ± 0.4 1.8 ± 0.2 1.5 ± 0.3 1.0 1.2 ± 0.07 1.5 ± 0.05 1.3 + 0.07 1.0 5.5 ± 0.5 5.5 ± 1.5 9.5 ± 1.5 LIFa 1.0 2.8 ± 1.2 2.7 ± 0.6 5.1 ± 1.6 NOa 8 ± 1.5 47 ± 2.5 20 ± 3 21 + 1.5 Table 60: reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in bone marrow macrophages of murine macrophages derived from bone marrow of BALB / mice were cultured by either 6 or 24 hours with 100 ng / ml of E coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide Access Gene Number AL050337 U05875 N _002310 Ü92971 Z29575 L31584 J03925 M64788 NM_0004850 D87451 AL049975 Unknown U39067 AK000942 Unknown AB040057 AB020719 AB007856 Unknown AL137376 Unknown AL137730 Unknown M90696 AK001143 Unknown AF038406 A 000315 M54915 D29011 AL034348 Unknown D87076 KIAA0239 protein AJ001403 J03925 Example 10 Anti-Sepsis / Anti-Inflammatory Activity Arrays of polynucleotides were used to determine the effect of cationic peptides on the transcriptional response of epithelial cells. The human epithelial cell line A549 was maintained in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS, Medicorp). A549 cells were plated in 100 mm tissue culture dishes at 2.5 x 10 6 cells / dish, cultured overnight and then incubated with 100 ng / ml E. coli 0111: B4 LPS (Sigma), without (control) or with 50 μ? / ??? of peptide or medium alone for 4 hours. After stimulation, the cells were washed once with buffered saline (PBS) with phosphate, treated with diethyl pyrocarbonate, and separated from the dish using a cell scraper. Total RNA was isolated using RNAqueous (Ambion, from Austin, Texas, United States). The RNA beads were re-suspended in RNase-free water containing Superase-In (RNase inhibitor); Ambion). DNA contamination was removed with the DNA-free kit from Ambion. RNA quality was determined by gel electrophoresis in 1% agarose gel. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which tumor necrosis factor-a (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-α. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E.W. , 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NF B). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Also, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and memory T cells through interaction with CCR6. The arrays of polynucleotides used were arrays of human operons (the identification number for the genome is PRHU04-S1), which consist of about 14,000 human oligos in duplicate. Probes were prepared from 10 ig of total RNA and marbed with dUTP marbed with Cy3 or Cy5. The probes were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Perkin Elmer array scanner. The image processing software (Imapolynucleo-tide 5.0, Marina Del Rey, California, United States) determines the average intensity of spots, average intensities, and background intensities. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS. In Table 1, the peptide, SEQ ID NO: 27, is shown to potently reduce the expression of many of the polynucleotides up-regulated by E. coli 0111: B4 LPS, as studied by micro-arrays of polynucleotides. Peptide (50 μg ml) and LPS (0.1 μg / ml) or LPS were only incubated with A549 cells for 4 hours and RNA was isolated. 5 μg of total RNA was used to make marseted Cy3 / Cy5 cDNA probes and hybridized in human operon arrays (PRHU04). The intensity of the unstimulated cells is shown in the third column of Table 1. The column "ratio: LPS / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS divided by the intensity of the unstimulated cells. The column "Relationship: LPS + ID 27 / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS and peptide divided between unstimulated cells. Table 61: Reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 g / ml of the peptide.

Example 11 Anti-Sepsis / Anti-Inflammatory Activity Polynucleotide arrays p were used to determine the effect of cationic peptides on transcriptional response of epithelial cells. The human epithelial cell line A549 was maintained in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS, Medicorp). A549 cells were plated in 100 mm tissue culture dishes at 2.5 x 10 6 cells / dish, cultured overnight and then incubated with 100 ng / ral of E. coli 0111: B4 LPS (Sigma), without (control) or with 50 pg / ml of peptide or medium only for 4 hours. After stimulation, the cells were washed once with buffered saline (PBS) with phosphate, treated with diethyl pyrocarbonate, and separated from the dish using a cell scraper. Total RNA was isolated using RNAqueous (Ambion, from Austin, Texas, United States). The RNA beads were resuspended in RNase-free water containing Superase-In (RNAse inhibitor, Ambion). DNA contamination was removed with the DNA-free kit from Ambion. RNA quality was determined by gel electrophoresis on a 1% agarose gel. The arrays of polynucleotides used were arrays of human operons (the identification number for the genome is PRHU04-S1), which consist of about 14,000 human oligos in duplicate. Probes were prepared from 10 ug of total RNA and marbed with dUTP marbed with Cy3 or Cy5. The probes were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Perkin Elmer array scanner. The image processing software (Imapolynucleo-tide 5.0, Marina Del Rey, California, United States) determines the average intensity of spots, average intensities, and background intensities. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS. In Table 1, the peptide, SEQ ID NO: 27, is shown to potently reduce the expression of many of the polynucleotides up-regulated by E. coli 0111: B4 LPS, as studied by micro-arrays of polynucleotides. Peptide (50 pg / ml) and LPS (0.1 μg ml) or LPS were only incubated with A549 cells for 4 hours and RNA was isolated. 5 μg of total RNA was used to make marseted Cy3 / Cy5 cDNA probes and hybridized in human operon arrays (PRHU04). The intensity of the unstimulated cells is shown in the third column of Table 1. The column "ratio: LPS / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS divided by the intensity of the unstimulated cells. The column "Relationship: LPS + ID 27 / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS and peptide divided between unstimulated cells. Table 62: reduction by peptide SEQ ID NO: 1 of TNF-cx production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 pg / ml of the peptide.

Table 63: Reduction by peptide SEQ ID NO: 1 of TNF-α production induced by E. coli LPS in murine bone marrow macrophages Bone marrow-derived macrophages from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 ug / ml of the peptide.

Table 64: reduction by peptide SEQ ID NO: 1 of TNF-OI production induced by E. coli LPS in bone marrow macrophages from murine macrophages derived from bone marrow from BALB / c mice were cultured by either 6 or 24 hours with 100 ng / ml of E. coli 0111: B4 LPS in the presence or absence of 20 μg / ml of the peptide.

Example 12 Anti-Sepsis / An i-Inflammatory Activity Polynucleotide arrays were used to determine the effect of cationic peptides on the transcriptional response of epithelial cells. The human epithelial cell line A549 was maintained in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS, edicorp). A549 cells were plated in 100 mm tissue culture dishes at 2.5 x 10 5 cells / dish, cultured overnight and then incubated with 100 ng / ml E. coli 0111: B4 LPS (Sigma), without (control) or with 50 pg / ml of peptide or medium only for 4 hours. After stimulation, the cells were washed once with buffered saline (PBS) with phosphate, treated with diethyl pyrocarbonate, and separated from the dish using a cell scraper. Total RNA was isolated using RNAqueous (Ambion, from Austin, Texas, United States). The RNA beads were resuspended in RNase-free water containing Superase-In (RNAse inhibitor, Ambion). DNA contamination was removed with the DNA-free kit from Ambion. RNA quality was determined by gel electrophoresis in 1% agarose gel. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which tumor necrosis factor-a (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-α. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, R.E.W., and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Likewise, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking in -defensins, suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of a-defensin, HNP-1 and HNP-2, have been indicated to have direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for immature dendritic cells and memory T cells through interaction with CCR6. The arrays of polynucleotides used were arrays of human operons (the identification number for the genome is PRHU04-S1), which consist of about 14,000 human oligos in duplicate. Probes were prepared from 10 g of total RNA and marborated with dUTP marbed with Cy3 or Cy5. The probes were purified and hybridized on glass slides printed overnight at 42 ° C and washed. After washing, the image was captured using a Perkin Elmer array scanner. The image processing software (Imapolynucleo-tide 5.0, Marina Del Rey, California, United States) determines the average intensity of spots, average intensities, and background intensities. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS. In Table 1, the peptide, SEQ ID NO: 27, is shown to potently reduce the expression of many of the polynucleotides up-regulated by E. col! 0111: B4 LPS, as studied by micro-arrays of polynucleotides. Peptide (50 g / ml) and LPS (0.1 g / ml) or LPS were only incubated with A549 cells for 4 hours and the RNA was isolated. 5 μg of total RNA was used to make marseted Cy3 / Cy5 cDNA probes and hybridized in human operon arrays (PRHU04). The intensity of the unstimulated cells is shown in the third column of Table 1. The column "ratio: LPS / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS divided by the intensity of the non-stimulated cells. stimulated. The column "Relationship: LPS + ID 27 / control" refers to the intensity of the expression of polynucleotides in cells stimulated with LPS and peptide divided between unstimulated cells. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood Cityr California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS. Results A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which the factor. of tumor necrosis (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the outer component of the bacterial membrane, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-a. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to their natural release during bacterial infections, treatment with antibiotics can also result in the release of the bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membr and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membr taken to self-promoted intake through the outer membrand access to the cytoplasmic membr Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, REW, and G. Diamond, 2000. The Role of Cationic Peptides in Innate Host Defenses Trends in Microbiology 8: 402-410; Hancock, REW, 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Diseases 1: 156-164), although it was not known if the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Likewise, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in one. increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of -defensin, HNP-1 and HNP-2, have been indicated for having direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for cells immature dendrites and T cells of memory through interaction with CCR6. The current sales of antibiotics are of the order of 26 billion US dollars around the world. However, the overuse and sometimes unjustified use of antibiotics have resulted in the evolution of new strains of bacteria resistant to antibiotics. Antibiotic resistance has become part of the medical landscape. Bacteria such as vancomycin-resistant Enterococcus, VRE-resistant Staphylococcus aureus and methicillin and MRSA can not be treated with antibiotics, and patients suffering from infections with such bacteria often die. The discovery of antibiotics has proven to be one of the most difficult areas for the development of new drugs and many large pharmaceutical companies have cut or completely stopped their antibiotic development programs. However, with the dramatic increase in resistance to antibiotics, including the emergence of non-treatable infections, there is a clear and unmet medical need for novel types of anti-microbial therapies and agents that impact on innate immunity would be one such agent classes. The innate immune system is an effective and evolved general defense system. The elements of innate immunity are always present at low levels and are activated very quickly when stimulated. Stimulation may include interaction of bacterial signaling molecules with recognition receptors of patterns on the surfaces of body cells or other disease mechanisms. Every day, humans are exposed to tens of thousands of potential pathogenic microorganisms through food and water they ingest, the air they breathe, and the surfaces, the pets and the people they touch. The innate immune system acts to prevent these pathogens from causing diseases. The innate immune system differs from the so-called adaptive immunity (which includes antibiotics and B and T lymphocytes specific to antigens) because it is always present, is immediately effective, and is relatively non-specific for any given pathogen. The adaptive immune system requires amplification of specific recognition elements and in this way it takes days to weeks to respond. Even when adaptive immunity is pre-stimulated by vaccination, it may take three or more days to respond to a pathogen, while innate immunity is available immediately or quickly (hours). Innate immunity involves a variety of effector functions including phagocyigotic cells, complement, etc., but is generally incompletely understood. In general terms, many innate immune responses are "triggered" by the ligation of microbial signaling molecules with pattern recognition receptors called Toll-like receptors on the surface of host cells. Many of these effector functions are grouped together in the inflammatory response. However, an overly severe inflammatory response can result in responses that are harmful to the body and, in an extreme case, sepsis and potentially death. The release of structural components of infection agents during an infection causes an inflammatory response, which when unattended can lead to a potentially lethal condition, sepsis. Sepsis occurs in approximately 780,000 patients in North America annually. Sepsis can develop as a result of community-acquired infections, such as pneumonia, or it can be a complication of the treatment of trauma, cancer or major surgery. Severe sepsis occurs when the body is overwhelmed by the inflammatory response and the organs of the body begin to fail. Up to 120,000 deaths occur annually in the United States due to sepsis. Sepsis can also involve pathogenic microorganisms or toxins in the blood (eg, septicemia), which is a leading cause of death among humans. Gram-negative bacteria are the organisms most commonly associated with such diseases. However, gram-positive bacteria are a cause of increasing infections. Gram-negative and gram-positive bacteria and their components can all cause sepsis. The presence of microbial components induces the release of pro-inflammatory cytokines of which tumor necrosis factor-a (TNF-a) is of extreme importance. TNF-a and other pro-inflammatory cytokines can then cause the release of other pro-inflammatory mediators and lead to an inflammatory cascade. Gram-negative sepsis is usually caused by the release of the external bacterial membrane component, lipopolysaccharide (LPS, also referred to as endotoxin). The endotoxin in blood, called endotoxemia, comes mainly from a bacterial infection, and can be released during treatment with antibiotics. Gram-positive sepsis can be caused by the release of bacterial cell wall components, such as lipoteichoic acid (LTA), peptidoglycan (PG), rhamnose-glucose polymers made by Streptococci, or capsular polysaccharides made by Staphylococcus. It has also been shown that bacterial DNA or other non-mammalian DNA, which unlike mammalian DNA frequently contains unmethylated cytosine-guanosine dimers (CpG DNA), induces septic conditions including the production of TNF-a. Mammalian DNA contains CpG dinucleotides at a much better frequency, often in a methylated form. In addition to its natural release during bacterial infections, treatment with antibiotics can also cause the release of bacterial cell wall components LPS and LTA and probably also bacterial DNA. This can then hinder the recovery of the infection or even cause sepsis. Cationic peptides are increasingly recognized as a form of defense against infection, although the major effects recognized in the scientific and patent literature are anti-microbial effects (Hancock, REW, and R. Lehrer, 1998. Cationic peptides: a new source of antibiotics, Trends in Biotechnology 16: 82-88). Cationic peptides that have anti-microbial activity have been isolated from a wide variety of organisms. In nature, such peptides provide a defense mechanism against microorganisms such as bacteria and yeasts. Generally, it is thought that these cationic peptides exert their anti-microbial activity on bacteria interacting with the cytoplasmic membrane, and in most cases forming channels or lesions. In gram-negative bacteria, they interact with 1PS to permeabilize the outer membrane, taken to self-promoted intake through the outer membrane and access to the cytoplasmic membrane. Examples of cationic anti-microbial peptides include indolicidin, defensins, cecropins, and magainins. Recently, it has been increasingly recognized that such peptides are effectors in other aspects of innate immunity (Hancock, RE, and G. Diamond, 2000. The role of cationic peptides in innate host defenses. Trends in Microbiology 8: 402- 410; Hancock, R.E.W., 2001. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infectious Diseases 1: 156-164), although it was not known whether the antimicrobial and effector functions were independent. Some cationic peptides have an affinity for bacterial ligation products, such as LPS and LTA. Such cationic peptides can suppress cytokine production in response to LPS, and in varying degrees can prevent a lethal shock. However, it has not been proven whether such effects are due to the ligation of the peptides to LPS and LTA, or due to a direct interaction of the peptides with host cells. Cationic peptides are induced, in response to challenge by microbes or microbial signaling molecules, such as LPS, by a regulatory pathway similar to that used by the mammalian immune system (involved Toll receptors and the transcription factor NFKB). Cationic peptides therefore seem to have a key role in innate immunity. Mutations that affect the induction of antibacterial peptides can reduce survival in response to bacterial challenge. Also, mutations of the Drosophila Toll path leading to reduced expression of anti-fungal peptides result in increased susceptibility to lethal fungal infections. In humans, patients with the specific granule deficiency syndrome who are completely lacking a-defensins suffer from frequent and severe bacterial infections. Other evidence includes the inductibility of some peptides by infectious agents, and the very high concentrations that have been recorded at sites of inflammation. Cationic peptides can also regulate cell migration, promote the ability of leukocytes to fight bacterial infections. For example, two human peptides of -defensin, HNP-1 and HNP-2, have been indicated for having direct chemotactic activity for murine and human T cells and monocytes, and human β-defensins appear to act as chemo-attractants for cells immature dendrites and T cells of memory through interaction with CCR6. Similarly, porcine cationic peptide PR-39 was found to be chemotactic for neutrophils. However, it is not clear if peptides from different structures and compositions share these properties. The only known cathelicidin in humans, LL-37, is produced by myeloid precursors, testes, human keratinocytes during inflammatory disorders and the epithelium of the respiratory tract. The characteristic aspect of the cathelicidin peptides is a high level of sequence identity in the prepro regions of the N-terminus, called the catelin domain. The cathelicidin peptides are stored as precursors of inactive pro-peptides which, when stimulated, are processed into active peptides. A "home" program was used to remove the bottom. The program calculates the intensity at 10% of the lower part for each sub-network and subtracts it for each network. Analysis was carried out with Genespring software (Redwood City, California, United States). The intensities for each spot were normalized by taking the mean intensity value of the population of spot values within a slide and comparing this value with the values of all the slides in the experiment. The relative changes observed with cells treated with peptide compared to control cells can be found in Tables 1 and 2. These Tables 1 and 2 reflect only those polynucleotides that demonstrated significant changes in the expression of the 14,000 polynucleotides that were tested for expression. altered The data indicate that the peptides have a diffused ability to reduce the expression of polynucleotides that were induced by LPS.

Claims

.claims 1. A method of stimulating the innate immunity in a subject, comprising administering to the subject a therapeutically effective amount of a peptide as identified in SEQ ID NOS: 1-4, 11, 18, 25, 32, 39, 46, 53, or 54, thereby stimulating an immune response. The method of claim 1, wherein the innate immunity is evidenced by the activation, proliferation, differentiation of host immune cells or activation of the MAP kinase path. 3. The method of claim 2, wherein the MAP kinases are MEK and / or ERK. 4. The method of claim 1, further comprising administering GM-CSF to the subject. 5. A method of stimulating the innate immunity in a subject having or at risk of having an infection comprising administering to the subject an antibiotic in combination with a peptide as identified in SEQ ID NOS: 1-4, 7, 11, 18, 25, 32, 39, 46, 53 or 54. The method of claim 1, wherein the peptide contains at least one amino acid that is a D-enantiomer. The method of claim 1, wherein the peptide is cyclic. The method of claim 1, wherein the peptide sequence is inverted. 9. The method of claim 1, further comprising administering an antibiotic to the subject. 10. The method of claim 9 wherein the antibiotic is selected from aminoglycosides, penicillins, cephalosporins, cerbacefemas, cephamycins, chloramphenicols, gliciclinas, licosamides, aminocyclitols, antimicrobial peptides cationic lipopeptides pomixinas, estreptogrami-nas, oxazoladinonas, lincosamides, fluoroquinolones , carbapene-mas, tetracyclines, macrolides, beta-lactams, carbapenems, mono-bactams, quinolones, tetracyclines, or glycopeptides. The method of claim 5, wherein the peptide has anti-inflammatory activity. 12. The method of claim 5, wherein the peptide has anti-sepsis activity. The method of claim 5, wherein the peptide contains at least one amino acid that is a D-enantiomer. The method of claim 5, wherein the peptide is cyclic. 15. The method of claim 5, wherein the sequence of the peptide is inverted. 16. The method of claim 5 wherein the antibiotic is selected from aminoglycosides, penicillins, cephalosporins, cerbacefemas, cephamycins, chloramphenicols, gliciclinas, licosamides, aminocyclitols, antimicrobial peptides cationic lipopeptides pomixinas, estreptogrami-nas, oxazoladinonas, lincosamides, fluoroquinolones , carbapene-mas, tetracyclines, macrolides, beta-lactams, carbapenems, mono-bactams, quinolones, tetracyclines, or glycopeptides. 17. A method of stimulating innate immunity in a subject having or at risk of having an infection, comprising administering to the subject GM-CSF in combination with a peptide as set forth in SEQ ID NOS: 1-4, 7 , 11, 18, 25, 32, 39, 46, 53 or 54. 18. The method of claim 17, wherein the peptide has anti-inflammatory activity. 19. The method of claim 17, wherein the peptide has anti-sepsis activity. The method of claim 17, wherein the peptide contains at least one amino acid that is a D-enantiomer. 21. The method of claim 17, wherein the peptide is cyclic. 22. The method of claim 17, wherein the peptide sequence is inverted.