WO2015194525A1 - Facteur de déclenchement d'une maladie inflammatoire chronique des adipocytes - Google Patents

Facteur de déclenchement d'une maladie inflammatoire chronique des adipocytes Download PDF

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WO2015194525A1
WO2015194525A1 PCT/JP2015/067248 JP2015067248W WO2015194525A1 WO 2015194525 A1 WO2015194525 A1 WO 2015194525A1 JP 2015067248 W JP2015067248 W JP 2015067248W WO 2015194525 A1 WO2015194525 A1 WO 2015194525A1
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chronic
onset
inflammatory disease
fat
gene
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PCT/JP2015/067248
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English (en)
Japanese (ja)
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優 石井
下村　伊一郎
船橋　徹
法一 前田
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国立大学法人大阪大学
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Priority to JP2016529350A priority Critical patent/JP6558645B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology

Definitions

  • the present invention relates to a trigger factor for fat chronic inflammatory disease, a fatty chronic inflammatory disease onset inhibitor, and a test method for fat chronic inflammatory disease.
  • Inflammation is a symptom in which an immune response is activated when a living body receives some harmful stimulus, thereby appearing in the living body.
  • the types of inflammation include acute inflammation with neutrophil-based cell infiltration and fibrin deposition as well as slow tissue destruction and tissue construction due to infiltration of lymphocytes, plasma cells, macrophages, and tissue growth. It is classified as chronic inflammation with modification. Inflammation is an important biodefense function, which is essential, but unnecessary or excessive (long-term) inflammatory reactions can exacerbate or cause new diseases.
  • chronic inflammation is a pathological condition common to lifestyle-related diseases such as obesity, metabolic syndrome, arteriosclerotic disease, and cancer, and is considered to be an important factor in Alzheimer's disease, renal failure, cirrhosis, and the like.
  • Acute inflammation causes inflammatory reactions such as fever, swelling, pain, and redness, but chronic inflammation can hardly be confirmed.
  • acute inflammation is often reversible and heals without restructuring the tissue, whereas chronic inflammation is caused by tissue fibrosis or inflammation cells such as macrophages. Entering, the cells of the tissue are enlarged and proliferated, the structure changes, causing dysfunction.
  • chronic inflammation has been considered as the etiology of many diseases, such as type II diabetes.
  • S100A8 / A9 is known to be associated with chronic inflammation (Patent Document 1, Non-Patent Document 1).
  • Patent Document 1 Non-Patent Document 1
  • these documents do not show the relationship between chronic inflammation and diabetes.
  • ethyl palmitate was continuously administered intravenously to mice, expression of S100A8 and S100A9 in epididymal adipose tissue was observed 4 hours after administration, and macrophage accumulation was observed 12 hours later.
  • Non-patent Document 2 It has been reported that S100A8 and S100A9 have been shown to contribute to the induction of macrophages into adipose tissue by palmitic acid (Non-patent Document 2). However, the animal model produced in Non-Patent Document 2 cannot be said to be a model showing chronic inflammation of adipose tissue.
  • the present invention aims to provide a trigger factor for the onset of fat chronic inflammatory disease, and provides an agent for suppressing the onset of fatty chronic inflammatory disease characterized by suppressing the trigger factor.
  • Another object of the present invention is to provide a method for predicting the onset of chronic fat inflammatory disease, characterized by measuring the expression level of the trigger factor.
  • the present inventors have succeeded in capturing the initial phenomenon of chronic inflammation by visualizing the chronification process of inflammation using a biological tissue imaging experimental system developed independently. Furthermore, S100A8 was identified as the first trigger factor for inducing this initial phenomenon, and the present invention was completed.
  • this invention consists of the following.
  • Trigger factor for the development of chronic fat inflammatory disease comprising S100A8.
  • 2. The trigger factor for the onset of chronic fat inflammatory disease according to item 1, wherein the trigger factor is a macrophage migration ability stimulating factor in adipose tissue.
  • 3. The trigger factor for the onset of chronic fat inflammatory disease according to item 1 above, wherein the trigger factor is an expression inducer of inflammatory cytokines and / or chemokines. 4).
  • An agent for inhibiting the onset of chronic fat inflammatory disease comprising as an active ingredient a substance that targets the trigger factor for the onset of chronic fat inflammatory disease according to any one of items 1 to 3. 5. 5. 5.
  • a test method for predicting the onset of fat chronic inflammatory disease or measuring the degree of progression of fat chronic inflammation characterized by measuring the expression level of S100A8 or S100A8 gene in a specimen. 9. In addition to the measurement of the expression level of S100A8 or S100A8 gene in a specimen, the expression level of at least one protein or gene of S100A9, inflammatory cytokine and / or chemokine is further measured. Inspection method described. 10. 11. The examination method according to item 10 above, wherein the inflammatory cytokine and / or chemokine is at least one selected from CCL2 / MCP-1, CCL3, IL-1 ⁇ , TNF- ⁇ , SAA3, CXCL1, CXCL5 and HMGB1. 11.
  • the expression level of S100A8 or S100A8 gene exceeds the level of healthy people, and the expression level of at least one protein or gene of S100A9, inflammatory cytokine and / or chemokine is at the level of healthy people 10.
  • S100A8 By collecting adipocytes at the time of high fat diet loading and measuring the molecular expression level, among various chemokines / cytokines and immune activators, only S100A8 increased its expression from 1 week of high fat diet loading. It was confirmed that Then, by measuring the expression level of S100A8, a test for predicting the onset of chronic fat inflammatory disease or measuring the degree of progression of fat chronic inflammation can be performed. In particular, morphological changes such as adipocyte hypertrophy and the expression of other inflammatory cytokines and chemokines such as S100A8 are observed at an early stage compared to S100A9.
  • the progression to fat chronic inflammatory diseases such as diabetes, hyperlipidemia, arteriosclerosis, etc. can be suppressed by dealing early.
  • Administration of a factor that suppresses S100A8, for example, an anti-S100A8 antibody can suppress immune cell migration and suppress the onset of chronic fatty inflammation.
  • FIG. 1 It is a result figure which shows the body weight of each mouse
  • Reference Example 1 It is a result figure which shows the blood glucose level of each mouse
  • Reference Example 1 It is a result figure which shows the fat cell diameter of each mouse
  • Reference Example 1 It is a result figure which shows the macrophage migration ability of each mouse
  • FIG. 6 is a diagram showing the results of confirming the expression levels of S100A8, S100A9, HMGB1, CCL2 / MCP-1, CCL3, and IL-1 ⁇ as alarmins, which are molecules that induce inflammatory responses, for each mouse.
  • S100A8 which is a molecule
  • CCL2 / MCP-1 about each mouse
  • S100A8 which is a molecule
  • Reference Example 2 It is a figure which shows the result of having confirmed the effect
  • Example 1 It is a figure which shows the result of having confirmed the effect
  • Example 2 It is a figure which shows the result of having confirmed the effect
  • Example 2 It is a figure which shows the result of having confirmed the effect
  • Example 4 It is a figure which shows the result of having confirmed the influence which acts on CCL2 / MCP-1, SAA3, CXCL1, and CXCL5 gene expression. (Example 3) It is a figure which confirmed about the LysM EGFP mouse
  • Example 4 It is a figure which confirmed about the LysM EGFP mouse
  • S100A8 is an early trigger of chronic inflammation in lifestyle-related diseases, and by suppressing this action, chronic and sustained inflammation is prevented, and it is a breakthrough that suppresses the onset of obesity and abnormal lipid metabolism. It can be a treatment method.
  • the present invention provides a trigger factor for the onset of chronic fat inflammatory disease comprising S100A8.
  • S100A8 the amino acid sequence of S100A8 and the DNA sequence encoding it are disclosed, for example, in Hum Genet (2002) 111: 310-313.
  • the chronic fat inflammatory disease includes the basic pathological conditions of chronic fat inflammation and metabolic syndrome.
  • obese adipose tissue not only changes in adipocytes themselves with adipocyte hypertrophy, but also angiogenesis, increase in extracellular matrix, infiltration and qualitative changes in immune cells such as macrophages, neutrophils, and T cells Inflammation changes due to.
  • specific examples of such fat chronic inflammatory diseases include diabetes, hyperlipidemia, arteriosclerosis and the like.
  • Adipocyte hypertrophy is observed in the early stages of obesity.
  • TNF- ⁇ In enlarged fat cells, TNF- ⁇ , CCL2 (chemokine [CC motif] ligand 2) / MCP-1 (Monocyte Chemoattractant Protein-1), IL-1, Production of inflammatory cytokines such as IL-6, IL-4, IL-10, and HMGB-1 is increased, and production of anti-inflammatory cytokines such as adiponectin is decreased.
  • CCL2 chemokine [CC motif] ligand 2
  • MCP-1 Monocyte Chemoattractant Protein-1
  • IL-1 Production of inflammatory cytokines such as IL-6, IL-4, IL-10, and HMGB-1 is increased, and production of anti-inflammatory cytokines such as adiponectin is decreased.
  • M1 macrophage classically activated macrophage
  • M2 macrophage alternatively activated macrophage
  • the type of macrophages of adipose tissue that is stimulated by S100A8 is not particularly limited, and examples thereof include M1 macrophages that are inflammatory macrophages.
  • Examples of inflammatory cytokines and / or chemokines in adipose tissue whose expression is enhanced by S100A8 in the present invention include those belonging to alarmin or DAMPs (danger-associated molecular patterns), CCL2 / MCP-1, CCL3, IL-1 ⁇ and TNF- ⁇ can be mentioned. Furthermore, serum amyloid A3 (SAA3), CXCL1 (chemokine (C-X-C-motif) ligand 1) and CXCL5 can be mentioned.
  • SAA3 serum amyloid A3
  • CXCL1 chemokine (C-X-C-motif) ligand 1
  • CXCL5 can be mentioned.
  • the trigger factor for the onset of chronic fatty inflammatory disease of the present invention also has a function as a macrophage migration ability stimulating factor and inflammatory cytokine and / or chemokine expression inducing factor in the adipose tissue as described above. Also included are macrophage migration-stimulating factors and a pro-inflammatory factor and / or chemokine expression inducer in adipose tissue consisting of S100A8.
  • the present invention further extends to a fat chronic inflammatory disease onset inhibitor that targets a trigger factor for the development of fat chronic inflammatory disease.
  • the agent for suppressing the onset of chronic fat inflammatory disease refers to a drug that prevents the onset of fat chronic inflammation or fat chronic inflammatory disease, prevents the progression of the disease, or treats it.
  • a substance that inhibits the function of S100A8 or the expression of the S100A8 gene can be mentioned. Examples thereof include an antibody against S100A8 and a nucleic acid that inhibits expression of the S100A8 gene, such as siRNA.
  • the substance may be a low molecular compound in addition to a high molecular compound such as a protein, peptide, or nucleic acid substance.
  • the pharmacologically acceptable carrier can be included in the fat chronic inflammatory disease onset inhibitor of the present invention.
  • the pharmacologically acceptable carrier used in the fat chronic inflammatory disease onset inhibitor include excipients, disintegrants or disintegrants, binders, lubricants, coating agents, dyes, diluents, Examples include bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, and adhesives.
  • the agent for inhibiting the onset of chronic fatty inflammatory disease of the present invention may be administered locally or systemically.
  • Formulations for parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous diluents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and organic ester compositions such as ethyl oleate, which are suitable for injection.
  • Aqueous carriers may include water, alcoholic aqueous solutions, emulsions, suspensions, saline and buffered media.
  • Parenteral carriers may include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, Ringer's lactic acid and binding oil.
  • Intravenous carriers may include, for example, fluid supplements, nutrients and electrolytes (eg, those based on Ringer's dextrose).
  • the fat chronic inflammatory disease onset inhibitor of the present invention may further contain a preservative and other additives such as antimicrobial compounds, antioxidants, chelating agents and inert gases.
  • the present invention further extends to a test method for predicting the onset of fat chronic inflammatory disease or measuring the progression of fat chronic inflammation, characterized by measuring the expression level of S100A8 or S100A8 gene in a specimen.
  • S100A8 is a trigger factor for the onset of fat chronic inflammatory disease
  • S100A8 or S100A8 gene the expression level of S100A8 or S100A8 gene
  • the onset of fat chronic inflammatory disease can be predicted.
  • S100A8 triggers the onset of chronic fat inflammatory disease
  • S100A9 is expressed with a delay.
  • other inflammatory cytokines and / or chemokines except S100A8 are also expressed late.
  • a test for measuring the progression of fat chronic inflammation can be performed by measuring the expression level of the S100A8 or S100A8 gene in the specimen.
  • the degree of progression of fat chronic inflammation can be measured by measuring the expression level of the S100A8 or S100A8 gene in the specimen.
  • the expression level of at least one S100A9, inflammatory cytokine and / or chemokine protein or gene among adipose tissue S100A9, inflammatory cytokine and / or chemokine in the specimen is measured. By doing so, the progress of fat chronic inflammation can be measured.
  • the expression level of the S100A8 or S100A8 gene exceeds the level of a healthy person, and at least one of the S100A9, inflammatory cytokine and / or chemokine protein of S100A9, inflammatory cytokine and / or chemokine
  • the progression of fat chronic inflammation can be measured by confirming that the gene expression level is at the level of a healthy person.
  • the inflammatory cytokine and / or chemokine of adipose tissue is alarmin or DAMPs, and examples of alarmin or DAMPs include CCL2 / MCP-1, CCL3, IL-1 ⁇ , TNF- ⁇ , SAA3, CXCL1, CXCL5, HMGB1, etc. Can be mentioned.
  • the expression level of the S100A8 or S100A8 gene exceeds the level of a healthy person, and at least one of S100A9, inflammatory cytokine and / or chemokine protein or gene among S100A9, inflammatory cytokine and / or chemokine
  • an inhibitor of the onset of chronic fat inflammatory disease consisting of a substance that inhibits the function of S100A8 or the expression of the S100A8 gene to patients with the progression of chronic fat inflammation whose expression level is normal Can prevent the onset or progression of fat chronic inflammation.
  • the test specimen is not particularly limited as long as it is a specimen capable of measuring the gene expression level.
  • the expression level of the S100A8 gene can be measured by methods such as RT-PCR, quantitative PCR, Northern blot, ELISA, Western blotting, in situ hybridization, immunohistochemical staining, and the like.
  • the expression level of the reporter gene depends on the type of reporter gene, it can be measured by fluorescence intensity, luminescence intensity, radioactivity intensity, and the like.
  • RAW264.7 cells were cultured using Dulbecco's modified Eagle medium (DMEM) supplemented with 10% cochlear fetal serum (FCS) and 1% penicillin / streptomycin (P / S).
  • DMEM Dulbecco's modified Eagle medium
  • FCS cochlear fetal serum
  • P / S penicillin / streptomycin
  • 3T3-L1 cells were cultured in DMEM supplemented with 10% FCS, 1% P / S and 0.5 mM mM 1-methyl-3-isobutylxanthine, 1M dexamethasone and 5 mg / mL insulin. After culturing for 48 hours, the maintenance medium used was DMEM supplemented with 10% FCS and 1% P / S.
  • Example 3 Effect of human or mouse S100A8 on adipocytes
  • Mouse fibroblast-derived established adipocytes (3T3-L1) were transformed into human or mouse genetically modified S100A8 (Giotto Biotech) 10 ⁇ g / mL, and endogenous.
  • PolyB polymyxin B
  • Example 4 Changes in immune cell dynamics after administration of S100A8 antibody
  • An adipocyte tissue was imaged on a LysM EGFP mouse on the fifth day after feeding the HF / HS diet. Prior to imaging, BODIPY staining was performed for adipose tissue and unlabeled Q-dots was administered intravenously for the vessel wall. LysM EGFP positive cells, which are myelomonocytic immune cells, were stained green. After anti-S100A8 antibody or IgG isotype as a control was administered to adipocytes, the kinetics of LysM EGFP positive cells was observed.
  • S100A8 is a trigger factor for the development of chronic fat inflammatory disease.
  • S100A8 is a trigger factor for the development of chronic fat inflammatory disease.
  • morphological changes such as adipocyte hypertrophy and the expression of other inflammatory cytokines and chemokines such as S100A8 are observed at an early stage compared to S100A9.
  • a factor that suppresses S100A8 for example, an anti-S100A8 antibody, can suppress immune cell migration and suppress the onset of chronic fatty inflammation.

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Abstract

La présente invention concerne un facteur de déclenchement de l'apparition d'une maladie inflammatoire chronique des adipocytes. L'invention concerne également un agent permettant de supprimer l'apparition d'une maladie inflammatoire chronique des adipocytes, caractérisé par la suppression de ce facteur de déclenchement. De plus, l'invention concerne un procédé permettant de prévoir l'apparition d'une maladie inflammatoire chronique des adipocytes, caractérisé par la mesure du niveau d'expression de ce facteur de déclenchement. Le test est effectué pour prédire l'apparition d'une maladie inflammatoire chronique des adipocytes ou pour mesurer le progrès de l'inflammation chronique des adipocytes par la mesure du niveau d'expression du S100A8 comme facteur de déclenchement le plus précoce induisant le phénomène d'inflammation chronique le plus précoce. L'expression du S100A8 s'observe particulièrement au stade de modifications morphologiques, telles que l'hypertrophie des adipocytes et à un stade plus précoce que dans l'expression d'autres cytokines et chimiokines inflammatoires, par exemple, S100A9. L'administration d'un facteur de suppression de S100A8, par exemple un anticorps anti-S100A8, peut supprimer la migration de cellules immunitaires et de supprimer l'apparition d'une inflammation chronique des adipocytes.
PCT/JP2015/067248 2014-06-16 2015-06-16 Facteur de déclenchement d'une maladie inflammatoire chronique des adipocytes WO2015194525A1 (fr)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
JP2011518126A (ja) * 2008-03-25 2011-06-23 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン ＩＫＫｉ阻害剤の処置方法およびスクリーニング方法、ならびに関連するＩＫＫｉ診断方法
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JP2011518126A (ja) * 2008-03-25 2011-06-23 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン ＩＫＫｉ阻害剤の処置方法およびスクリーニング方法、ならびに関連するＩＫＫｉ診断方法
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