WO2007121963A1 - Méthodes pour soulager une maladie liée à une activation affaiblie de mastocytes - Google Patents

Méthodes pour soulager une maladie liée à une activation affaiblie de mastocytes Download PDF

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WO2007121963A1
WO2007121963A1 PCT/EP2007/003535 EP2007003535W WO2007121963A1 WO 2007121963 A1 WO2007121963 A1 WO 2007121963A1 EP 2007003535 W EP2007003535 W EP 2007003535W WO 2007121963 A1 WO2007121963 A1 WO 2007121963A1
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phenyl
hydroxy
methoxy
hydrazid
benzyliden
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PCT/EP2007/003535
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English (en)
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Florian Lang
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Merck Patent Gmbh
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    • 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
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • Mast cells express a large number of IGE receptors (Fc ⁇ RI) and largely account for the IgE dependent allergic reactions [Kawakami and GaIIi 2002; Kawakami and Kitaura 2005], such as allergic rhinitis [Pawankar 2005], asthma [Bradding 2003], anaphylactic and delayed hypersensitivity [Askenase et al., 1983; Conti et al., 1992; GaIIi et al., 2005; Van Loveren et al., 1983].
  • Mast cells release a variety of cytokines and thus regulate the function of other inflammatory cells such as neutrophils and T cells [Asada et al., 1997; Biedermann et al., 2000; GaIIi et al., 2005; GaIIi and Nakae 2003; Hill et al., 1996; Nakae et al., 2005; Nakae et al., 2006].
  • Mast cell function is under tight regulation.
  • Activation of the mast cells involves the stimulation of the PI3 kinase pathway [Andrade et al., 2004; Gilfillan and Tkaczyk 2006; Wymann et al., 2003] and is suppressed by glucocorticoids [Andrade et al., 2004; Collado-Escobar et al., 1990; Fushimi et al., 1998; Krishnaswamy et al., 1997; Matsuda et al., 2005; Mazingue et al., 1978; Robin et al., 1985; Wershil et al., 1995].
  • Activation of mast cells further involves activation of Ca 2+ channels [Bradding et al., 2003; Buess et al., 1999; Dernick et al., 2003; Duffy et al., 2001a; Duffy et al., 2001b; Kahr et al., 2004; Mazurek et al., 1980; Stokes et al., 2004], K + channels [Bradding et al., 2003; Bradding 2005; Duffy et al., 2005; Mark et al., 2004] and Cl " channels [Duffy et al., 2001a; Duffy et al., 2001b].
  • Signalling molecules downstream of PI3kinase include the serum and glucocorticoid inducible kinase SGK1 [Lang and Cohen 2001], which is expressed in all tissues tested [Waldegger et al., 1997].
  • SGK1 has been shown to regulate a wide variety of ion channels [Lang et al., 2003].
  • the kinase contributes to the regulation of salt appetite [Vallon et al., 2005], renal electrolyte excretion [Huang et al., 2004; Wulff et al., 2002] and blood pressure [Huang et al., 2006].
  • the current invention elucidates the role of SGK1 in mast cell function. It is shown for the first time that SGK1 is involved in the regulation of mast cells by the PI3 kinase pathway and plays a pivotal role in the stimulation of mast cells.
  • Kinases activated through the PI3 kinase pathway include the serum- and glucocorticoid-inducible kinase 1 (SGK1).
  • Ca 2+ entry following Ca 2+ depletion was significantly reduced in sgk1 'A BMCMC when compared to sgk1 +/+ BMCMC and this points to a defective activation of the Ca 2+ release activated Ca 2+ channel I C R A C- Accordingly, Ca 2+ sensitive K + channels were activated by IgE-DNP in sgk1 +/+ BMCMC but not in sgk1 'A BMCMC.
  • Trinitrochlorobenzene- induced contact hypersensitivity reaction has been tested in sgk1 +/+ and sgkT ⁇ mice.
  • TMCB Trinitrochlorobenzene
  • the current unexpected findings make serum and glucocorticoid inducible kinase-1 , modulators of SGK-1 activity and especially antagonists of SGK-1 activity important for the therapy of allergic reaction and other diseases driven by mast cell activity.
  • the current invention delivers a method for inhibiting activation of mast cells by contacting said mast cells with substances that inhibit glucocorticoid inducible kinase and thereby modulate the PI3 kinase dependent ion channel regulation and function.
  • An especially useful molecular target for inhibiting activation of mast cells according to this invention are glucocorticoid inducible kinases selected from the group consisting of: SGK1 , SGK2, SGK3.
  • mast cell activation dependent disorders Moreover a method for treating mast cell activation dependent disorders is readily envisible and this does require to administering substances that inhibit SGK1 to patients in need of such a treatment.
  • the preparation of a medicament on the basis of an SGK1 inhibitor is generally known in the art.
  • Preferred disorders that involve mast cell activation are but are not limited to allergic reaction, allergic rhinitis, anaphylactic and delayed hypersensitivity, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn ' s disease, irritable bowel syndrome or male infertility.
  • the listed disorders would greatly benefit from a treatment with SGK1 inhibiting or modulating compounds.
  • Modulating SGK1 compounds may be prefered in instances where the complete inhibition of SGK1 is not required and controlled residual SGK1 activity is needed.
  • the treatment of diseases selected from the group consisting of allergic reaction, allergic rhinitis, anaphylactic and delayed hypersensitivity, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn ' s disease, irritable bowel syndrome or male infertility may greatly benefit from the application of SGK1 modulators.
  • SGK directed treatment Prior to the application of SGK directed treatment it may be useful to examine the SGK1 status of a patient suffering from a mast cell activation dependent disorder and this is performed by measuring the up-regulated expression of SGK1 , SGK2 or SGK3 in mast cells derived from tissue samples and specimens of the patient.
  • SGK1 protein variant predisposes for disease. Therefore a method for determining mast cell activation dependent disorders by measuring the up-regulated expression of a selected single nucleotide polymorph variant of SGK1 in mast cells derived from tissue samples and specimens of risk patients may be used. SGK1 based diagnosis may be especially useful for evaluating human inflammatory disorder or human male infertility. The present invention provides evidence that SGK is involved in the activation of mast cells.
  • SGK serum glucocorticoid inducible kinases
  • the method comprises the following steps: (i) providing a recombinant pre-activated phosphorylated SGK protein (ii) providing an SGK substrate polypeptide together with ATP (iii) providing an inhibitor of glucocorticoid inducible kinases, and (iv) evaluating SGK activity by measuring phosphorylation of the substrate.
  • the SGK protein is selected from the group of SGK1 , SGK2 or SGK3 or that alternatively or in addition the selected single nucleotide polymorph variant of SGK may used as well.
  • the invention delivers a method for determining the progression, regression or onset of mast cell activation driven disorders by measuring the up-regulated expression and activation of SGK1 , SGK2 or SGK3 and selected single nucleotide polymorph variants in isolated human tissue samples and specimens.
  • the claimed methodes are well suited for the diagnosis of disease, wherein the disease is selected from the group consisting of allergic reaction, allergic rhinitis, anaphylactic and delayed hypersensitivity, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn ' s disease, irritable bowel syndrome or male infertility..
  • disorders selected from the group consisting of allergic reaction, allergic rhinitis, anaphylactic and delayed hypersensitivity, psoriasis, atopic dermatitis, rheumatoid arthritis, Crohn ' s disease, irritable bowel syndrome or male infertility.
  • the present study reveals a role of the serum and glucocorticoid inducible kinase SGK1 in the regulation of ion channel activity and function of mast cells. Distinct functional differences of mast cells are seen in gene targeted mice lacking SGK1 ⁇ sgkV' ' ) and their wild type littermates (sgk1+/+). Deficiency of SGK1 blunts the capacity of Ca 2+ entry and reflects that I C RAC i s leading to subsequent impairment of Ca 2+ dependent K + channel activation. Most importantly, the sgki ⁇ ' mice completely lack the early, mast cell dependent, response to TNCB, which induces delayed type hypersensitivity reactions
  • PI3 kinase has been suggested to target the TRPV2 Ca 2+ channel [Tseng et al., 2004].
  • SGK1 has previously been shown to increase the cell membrane abundance and activity of the Ca 2+ channel TRPV5 [Embark et al., 2004; Palmada et al., 2005] and SGK1 may have a similar stimulating effect on TRPV2.
  • SGK1 The molecular identity of the SGK1 regulated mast cell K + channels is similarly elusive. In other systems, SGK1 has been shown to activate several different K + channels [Baltaev et al., 2005; Embark et al., 2003; Embark et al., 2004; Gamper et al., 2002; Henke et al., 2004; Palmada et al., 2003; Ullrich et al., 2005; Warntges et al., 2002; Yoo et al., 2003; Yun et al., 2002b].
  • SGK1 function is not limited to the regulation of ion channels but has a known influence on further transport systems, including the NaVH + exchanger NHE3 [Yun et al., 2002a; Yun 2003], several amino acid transporters [Boehmer et al., 2003b; Boehmer et al., 2003a], glucose transporters [Dieter et al., 2004] and the Na + /K + -ATPase [Henke et al., 2004; Setiawan et al., 2002; Verrey et al., 2003; Zecevic et al., 2004]. Deranged regulation of those transporters maybe the molecular basis for the functional defect of mast cells from SGK1 knockout animals.
  • SGK1 function is not limited to the basic functions of mast cells but participates in their regulation by hormones and mediators.
  • SGK1 is genomically unregulated by glucocorticoids [Firestone et al., 2003], mineralocorticoids [Chen et al., 1999; Naray-Fejes-Toth et al., 1999; Shigaev et al., 2000], cell shrinkage [Waldegger et al., 1997], gonadotropins [Alliston et al., 1997; Alliston et al., 2000; Gonzalez-Robayna et al., 2000; Richards et al., 1995], and TGFB [Lang et al., 2000; Waldegger et al., 1999].
  • the kinase is activated by IGF 1 and insulin through the phosphatidyl-inositide 3 (PI3) kinase and phospho-inositide- dependent kinase PDK1 [Alessi et al., 1996; Alessi and Cohen 1998; Divecha et al., 1991 ; Gamper et al., 2002; Kobayashi and Cohen 1999; Kotani et al., 1994; Park et al., 1999].
  • PI3 phosphatidyl-inositide 3
  • PDK1 phospho-inositide- dependent kinase
  • mast cells cultured from bone marrow express CD117, CD34 and Fc ⁇ RI, i.e. the receptors typically expressed by mast cells.
  • BMCMC bone marrow
  • the forward and side scatter in cultured mast cells from sgk1 +/+ and sgkT A mice is shown in Figure 2.
  • the forward scatter is slightly but significantly smaller in sgk1 'A BMCMC than in sgk1 +/+ BMCMC, pointing to a slightly smaller cell volume.
  • the side scatter is slightly but significantly smaller in sgki ⁇ BMCMC than in sgk1 +/+ BMCMC, pointing to a slight decrease of granulation.
  • Furo-2 fluorescence reveals that Ca 2+ entry following Ca 2+ depletion is significantly smaller in sgkT ⁇ BMCMC than in sgk1 +/+ BMCMC, pointing to defective activation of the Ca 2+ release activated Ca 2+ channel I C RAC in sgkT A mice.
  • Patch clamp reveals the activation of Ca 2+ sensitive K + channels by IgE-DNP in sgk1* /+ BMCMC, an effect lacking completely in sgk1 v' BMCMC.
  • the channels are inhibited by clotrimazole, a known blocker of Ca 2+ sensitive K + channels.
  • Trinitrochlorobenzene -induced contact hypersensitivity reaction has been tested in both, sgk1 +/+ and sgk1 'A mice.
  • TMCB Trinitrochlorobenzene
  • mice lacking SGK1 have been generated as described previously [Wulff et al., 2002].
  • a conditional targeting vector was generated from a 7-kb fragment encompassing the entire transcribed region on 12 exons.
  • the neomycin resistance cassette was flanked by two loxP sites and inserted into intron 11.
  • Exons 4-11 which code for the Sgk1 kinase domain, were "floxed” by inserting a third loxP site into intron 3.
  • Targeted R1 ES cells were transiently transfected with Cre recombinase.
  • a clone with a recombination between the first and third loxP site (type I recombination) was injected into C57BL/6 blastocytes.
  • Male chimeras were bred to 129/SvJ females.
  • Heterozygous sg/c ⁇ -deficient mice were backcrossed to 129/SvJ wild-type mice for two generations and then intercrossed to generate homozygous sgkr ⁇ and Sgk1 +/+ littermates.
  • sgk1 +l+ and sgkT 1' mice were injected with dexamethasonephosphate disodiumsalt (Sigma, Taufkirchen, Germany; dissolved in 0.9% saline) at a dose of 10 ⁇ g/g BW for four consecutive days at 8 pm.
  • sgk1 ⁇ ' ⁇ and sgk1 +l+ mice injected with 0.9% saline alone served as controls.
  • Mice had free access to a standard mouse diet (Altromin diet 1310, Heidenau, Germany) and tap water.
  • the animals were fasted 16 hours on wire grids prior to the experiments with free access to tap water.
  • the KCNQ1 K + channel inhibitor 293B was applied as a single bolus intravenous injection at a dose of 5 ⁇ g/g BW 30 minutes before the experiment.
  • Example 2 Quantitative real-time PCR was used to determine the effect of glucocorticoids on SGK1 transcript levels, gastric tissue was quickly removed and frozen in liquid nitrogen. Automated disruption and homogenization of frozen tissue was performed using the MagNa Lyser Instrument TM (Roche Diagnostics, Mannheim, Germany). For each sample one-way special tubes were filled with ceramic beads, 20-30 mg of frozen tissue and 600 ⁇ l of RLT- buffer (Qiagen, Hilden, Germany). Cleared cell lysate was transferred for further RNA purification process (RNAeasy Mini Kit, Qiagen, Hilden, Germany).
  • RNA was reverse transcribed to cDNA utilizing the reverse transcription system (Bioscience, USA) with oligo(dT) primers according to the manufacturer's protocol.
  • reverse transcription system Bioscience, USA
  • oligo(dT) primers according to the manufacturer's protocol.
  • quantitative real-time PCR with the LightCycler System TM (Roche Diagnostics, Mannheim, Germany) was established.
  • PCR reactions for mSGK1 were performed in a final volume of 20 ⁇ l containing 2 ⁇ l cDNA, 2.4 ⁇ l MgCI 2 (3 ⁇ M), 1 ⁇ l primermix (0.5 ⁇ M of both primers), 2 ⁇ l cDNA Master SybrGreen I mix (Roche Molecular Biochemicals, Mannheim, Germany) and 12.6 ⁇ l DEPC treated water.
  • the transcript levels of the housekeeping gene mGAPDH were determined in each sample using a commercial primer kit (Search LC, Heidelberg, Germany).
  • PCR reactions for GAPDH were performed in a final volume of 20 ⁇ l containing 2 ⁇ l cDNA, 2 ⁇ l primer mix (Search LC, Heidelberg, Germany), 2 ⁇ l cDNA Master Sybr Green 5 I mix (Roche Molecular Biochemicals, Mannheim, Germany) and 14 ⁇ l DEPC treated water.
  • Amplification of the target DNA was performed during 35 cycles of 95°C for 1 Os 1 68 0 C for 10s and 72 0 C for 16s, each with a temperature transition rate of 20°C/s and a secondary target temperature of 58°C with a step size of 10 0.5 0 C.
  • Melting curve analysis was performed at 95 0 C Os, 58°C 10s, 95°C Os to determine melting temperatures of primer dimers and the specific PCR products. Melting curve analysis confirmed the amplified products, which were then separated on 1.5% agarose gels to confirm the expected size (406 bp). Finally, results were calculated as a ratio of the target vs. house keeping
  • mSGK1 sense 5' TGT CTT GGG GCT GTC CTG TAT G 3'
  • mSGK1 antisense 5' GCT TCT GCT GCT TCC TTC ACA C 3'
  • Bone marrow derived cultured mast cells were isolated from bone marrow of 12 weeks old male sgk1 +/+ and sgk1 'A naive mice. The cells were cultured for 4 weeks in RPMI 1640 (GIBCO, Carlsbad) containing 10% FCS, 1% penicillin/streptomicin, 0.5 ⁇ g IL-3 (RD systems, Wiesbaden- Nordenstadt) and 1 ⁇ g c-kit ligand (SCF, BIOZOL, Eching, Germany).
  • BMMCs were activated by sensitization with monoclonal mouse IgE Ab (1 :100, 12 ⁇ g/ml/ 1 Ox 6 cells, clone SPE-7, Sigma Aldrich, Kunststoff) overnight in culture medium and challenged accutely with (100ng/ml) DNP-HSA (dinitrophenyl -human serum albumin, Sigma Aldrich, Kunststoff) [Bradding et al., 2003].
  • FceRI e Bioscience/NatuTec Gmbh, Frankfurt
  • CD117 kit BD Pharmingen, Heidelberg
  • CD34 BD Pharmingen, Heidelberg
  • TNCB (Sigma Aldrich, Kunststoff) was used to induce delayed type hypersensitivity reactions (DTHRs), which are strictly dependent on hapten- specific, type 1 memory T cells and are associated with a strong infiltrate of polymorphic neutrophils PMNs [Biedermann et al., 2000; Pichler et al., 2005]. These memory T cells lead to CHSRs when the hapten is applied to the skin of sensitized mice [Asada et al., 1997].
  • mice were challenged with 1 % TNCB (20 ⁇ l of a 1 :9 mixture of acetone/olive oil) on both sides of the ear.
  • 1 % TNCB (20 ⁇ l of a 1 :9 mixture of acetone/olive oil)
  • acetone is an irritant, whereas it is used solely as a solvent in the 1 % TNCB solution.
  • Specific ear swelling was determined by measuring ear thickness with a micrometer (Oditest ®;Kroeplin) before and 4, 8, 12 and 48 h after TNCB challenge. Data are expressed as a change in ear swelling comparing to thickness before treatment, (delta ⁇ m).
  • ear tissue was collected 48 h after TNCB challenge and sections were stained with hematoxylin and eosin.
  • the currents were recorded by an EPC-9 amplifier (Heka, Lambrecht, Germany) using Pulse software (Heka) and an ITC-16 Interface (Instrutech, Port Washington, N. Y., USA).
  • Whole-cell currents were determined at eleven successive 700-ms square pulses from the -20 mV holding potential to potentials between -100 mV and +80 mV. The current values were 3 kHz low-pass filtered.
  • the pipette solution contained (in mM): 115 Na-gluconate, 10 NaCI, 1 MgATP, 1 EGTA, and 5 HEPES/NaOH (pH 7.4) and was used in combination with NaCI and Cl ' -free Ringer solutions (see above).
  • the offset potentials between both electrodes were zeroed before sealing.
  • the potentials were corrected for liquid junction potentials as estimated according to Barry & Lynch [Barry and Lynch 1991].
  • the original whole-cell current traces are depicted without filtering (acquisition frequency of 5 kHz) and currents of the individual voltage square pulses are superimposed.
  • the applied voltages refer to the cytoplasmic face of the membrane with respect to the extracellular space.
  • the inward currents defined as flow of positive charge from the extracellular to the cytoplasmic membrane face, are negative currents and depicted as downward deflections of the original current traces.
  • Fura-2 fluorescence was utilized for cytosolic Ca 2+ determinations. Intracellular Ca 2+ measurements were performed as described [Tanneur et al., 2002]. Retinoblastoma cells were loaded with Fura-2 (2.5 ⁇ M- Molecular Probes, Goettingen, Germany) for 30 minutes at 37°C. Fluorescence measurements were carried out with an inverted phase-contrast microscope (Axiovert 100, Zeiss, Oberkochen, Germany). Cells were excited alternatively at 340 and 380 nm and the light was deflected by a dichroic mirror into the objective (Fluar 40 ⁇ /1.30 oil, Zeiss, Oberkochen, Germany).
  • Emitted fluorescence intensity was recorded at 505 nm and data acquisition was performed by Axon Imaging Workbench (Axon Instruments, Foster City, USA). Experiments were made prior to, during and following exposure to nominally Ca 2+ free solution (5 mM EGTA added). In the absence of Ca 2+ the intracellular Ca 2+ stores were depleted by inhibition of the vesicular Ca 2+ pump by thapsigargin (1 ⁇ M, Molecular Probes).
  • Example 7 SGK1 inhibiting and modulating compounds
  • R 1 , R 5 is either H, OH, OA, OAc or Methyl
  • R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 is either
  • R 11 H or CH 3 , A Alkyl with 1 , 2, 3 or 4 C-atoms,
  • R 1 , R 2 , R 3 R 4 , R 5 is either H, A, OH, OA, Alkenyl, Alkinyl, NO 2 , NH 2 , NHA, NA 2 ,
  • R 6 , R 7 is either H, A, Hal, OH, OA or CN, R 8 , R 9 is either H or A,
  • Het Is a saturated or unsaturated heterocycle with 1 to 4 N-, O- and/or S-atoms, substituted by one or several Hal, A, OA,
  • a Alkyl with 1 to 10 C-atoms, wherein 1-7 H-atoms may be replaced by F and/or Chlorine,
  • X 1 X 1 is either NH or is missing
  • SGK1 nucleotide polymorphism is demonstrated by the sequences ...aattacattgCgcaacccag.., whereas the nucleotide sequence representing a another population is....aattacattgTgcaacccag.... Both sequences are available through accession number Gl 2463200 Position 2071.
  • the exon 8 sequences of facultative patients with mast cell overactivity are either homozygot ..tactgaC_ttcggact..or....tactgaTttcggact....or heterozygot .tactgaC_ttcggact...and...tactgaTttcggact ..
  • the sequences are available through accession number NM 005627.2, Position 777.
  • Boehmer C Henke G, Schniepp R, Palmada M, Rothstein JD, Broer S, Lang F: Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. J Neurochem 2003a;86:1181-1188.
  • Boehmer C Okur F, Setiawan I, Broer S, Lang F: Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Biochem Biophys Res Commun 2003b;306:156-162.
  • Bradding P The role of the mast cell in asthma: a reassessment. Curr Opin Allergy Clin Immunol 2003;3:45-50.
  • Bradding P Mast cell ion channels. Chem Immunol Allergy 2005;87:163-178. Bradding P, Okayama Y, Kambe N, Saito H: Ion channel gene expression in human lung, skin, and cord blood-derived mast cells. J Leukoc Biol 2003:73:614-620. Buess M, Engler O, Hirsch HH, Moroni C: Search for oncogenic regulators in an autocrine tumor model using differential display PCR: identification of novel candidate genes including the calcium channel mtrp ⁇ . Oncogene 1999;18:1487-1494. Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL,
  • Theoharides TC Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 2005; 174:7665-7675. Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D: Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci U S A 1999;96:2514- 2519.
  • Duffy SM, Cruse G, Lawley WJ, Bradding P Beta2-adrenoceptor regulation of the K+ channel iKCai in human mast cells. FASEB J 2005;19:1006-1008.
  • Duffy SM, Lawley WJ, Conley EC, Bradding P Resting and activation- dependent ion channels in human mast cells. J Immunol 2001 a;167:4261- 4270.
  • Embark HM Setiawan I, Poppendieck S, van de Graaf SF, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC 1 Bindels RJ, Lang F: Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cell Physiol Biochem 2004;14:203-212. Feng Y, Wang Q, Wang Y, Yard B, Lang F: SGK1 -mediated fibronectin formation in diabetic nephropathy.
  • FSH Follicle-Stimulating hormone
  • Kawakami T, GaIIi SJ Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2002;2:773-786.
  • Kawakami T, Kitaura J Mast cell survival and activation by IgE in the absence of antigen: a consideration of the biologic mechanisms and relevance.
  • Kobayashi T, Cohen P Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 1999;339:319-328.
  • PDK1 3-phosphoinositide-dependent protein kinase-1
  • Naray-Fejes-Toth A Canessa C, Cleaveland ES, Aldrich G, Fejes-Toth G: Sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial Na + channels. J Biol Chem 1999;274:16973-16978. Palmada M, Boehmer C, Akel A, Rajamanickam J, Jeyaraj S, Keller K, Lang F: SGK1 kinase upregulates GLUT1 activity and plasma membrane expression. Diabetes 2006;55:421-427.
  • Parekh AB Penner R: Store depletion and calcium influx. Physiol Rev 1997;77:901-930. Park J, Leong ML 1 Buse P 1 Maiyar AC, Firestone GL, Hemmings BA: Serum and glucocorticoid-inducible kinase (SGK) is a target of the Pl 3-kinase- stimulated signaling pathway. EMBO J 1999; 18:3024-3033.
  • Pawankar R Mast cells in allergic airway disease and chronic rhinosinusitis. Chem Immunol Allergy 2005;87:111-129.
  • Tanneur V Tanneur V, llgaz D, Duranton C, Fillon S, Gamper N, Huber SM, Lang F:
  • Waldegger S Klingel K, Barth P, Sauter M, Rfer ML, Kandolf R, Lang F: h- sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 1999;116:1081-1088. Warntges S, Friedrich B, Henke G, Duranton C, Lang PA, Waldegger S, Meyermann R, Kuhl D, Speckmann EJ, Obermuller N, Witzgall R, Mack AF, Wagner HJ, Wagner A, Broer S, Lang F: Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase
  • Dexamethasone or cyclosporin A suppress mast cell-leukocyte cytokine cascades. Multiple mechanisms of inhibition of IgE- and mast cell-dependent cutaneous inflammation in the mouse. J Immunol 1995; 154: 1391 -1398.
  • NHERF2 NHERF2
  • Figure 1 Cell surface receptor expression in cultured mast cells from sgk1* /+ and sgk1 m/' mice
  • BMCMC bone marrow mast cells
  • Figure 2 Forward and side scatter in cultured mast cells from sgk1 +/+ and sgk1 ⁇ ' ⁇ mice.
  • Figure 3 Ca 2+ entry into cultured mast cells from sgk1 +/+ and sgk1 m/ ⁇ mice.
  • Figure 4 Activation of Ca 2+ sensitive K + channels in cultured mast cells from sgk1 +/+ and sgkT' ' mice.
  • A. Mean I-V relationships ( ⁇ SEM, n 4) of currents in cultured bone marrow mast cells (BMCMC) from SGK1 knockout mice (sgr/cf ⁇ , right panel) and their wild type littermates (sgk1 +/+ , left panel) prior to (open circles) and following (closed triangles) activation with IgE-DNP in the absence (closed triangles) and presence (closed squares) of clotrimazole.
  • BMCMC bone marrow mast cells
  • B. Mean whole-cell conductance ( ⁇ SEM, n 4-6) obtained from cultured bone marrow mast cells (BMCMC) from SGK1 knockout mice (sgr/c7 'A , black barsj and their wild type littermates ⁇ sgk1 +/+ , white bars) prior to (control) and following exposure to IgE-DNP (IgE) and/or clotrimazole (CTZ) * indicates significant difference (p ⁇ 0.05; ANOVA).
  • Figure 5 Ear tissue from sgk1 +/ * and sgk1 '/m mice prior to and following Trinitrochlorobenzene -induced contact hypersensitivity reaction.
  • Sections of ear tissue from SGK1 knockout mice (sgk1 'A , left panel) and their wild type littermates (sgk1 +/+ , right panel) 8 hours following (lower panels) stimulation with Trinitrochlorobenzene (TNCB).
  • TMCB Trinitrochlorobenzene
  • FIG. 6 Ear swelling of sgk1 +/ * and sgAT A mice prior to and following Trinitrochlorobenzene -induced contact hypersensitivity reaction.

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Abstract

L'invention concerne une méthode pour soulager des troubles qui dépendent de l'activation de mastocytes comprenant la mise en contact de mastocytes qui expriment une kinase inductible par sérum et par glucocorticoïde (SGK) avec une substance qui module la kinase inductible par glucocorticoïde, et module ainsi la régulation et la fonction du canal ionique dépendant de la kinase PI3. En outre, l'invention concerne des méthodes pour diagnostiquer et identifier des composés utiles pour détecter ou traiter une maladie inflammatoire.
PCT/EP2007/003535 2006-04-25 2007-04-23 Méthodes pour soulager une maladie liée à une activation affaiblie de mastocytes WO2007121963A1 (fr)

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EP06008620 2006-04-25
EP06008620.4 2006-04-25

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WO2007121963A1 true WO2007121963A1 (fr) 2007-11-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014775A1 (fr) 2009-07-31 2011-02-03 The Brigham And Women's Hospital, Inc. Modulation de l’expression de sgk1 dans les cellules th17 pour moduler les réponses immunitaires médiées par th17
US11103486B2 (en) 2011-05-19 2021-08-31 The Johns Hopkins University Treatment of autoimmune disorders and infections using antagonists of SGK1 activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011681A1 (fr) * 2003-07-29 2005-02-10 Smithkline Beecham Corporation Composes chimiques
DE10346913A1 (de) * 2003-10-09 2005-05-04 Merck Patent Gmbh Acylhydrazonderivate
WO2005094796A2 (fr) * 2004-03-11 2005-10-13 Merck Patent Gmbh Methodes d'interference avec la fibrose

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011681A1 (fr) * 2003-07-29 2005-02-10 Smithkline Beecham Corporation Composes chimiques
DE10346913A1 (de) * 2003-10-09 2005-05-04 Merck Patent Gmbh Acylhydrazonderivate
WO2005094796A2 (fr) * 2004-03-11 2005-10-13 Merck Patent Gmbh Methodes d'interference avec la fibrose

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Impaired mast cell activation in geneTarget mice lacking the Serum and Glucocorticoid inducible kinase SGK1", INTERNET ARTICLE, 8 December 2006 (2006-12-08), XP002443190, Retrieved from the Internet <URL:http://www.adf-online.de/src/adf/ag_mastzellen_programm_2006.pdf> [retrieved on 20070718] *
WYMANN M P ET AL: "Phosphoinositide 3-kinase in disease: timing, location, and scaffolding", CURRENT OPINION IN CELL BIOLOGY, CURRENT SCIENCE, LONDON, GB, vol. 17, no. 2, April 2005 (2005-04-01), pages 141 - 149, XP004869317, ISSN: 0955-0674 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014775A1 (fr) 2009-07-31 2011-02-03 The Brigham And Women's Hospital, Inc. Modulation de l’expression de sgk1 dans les cellules th17 pour moduler les réponses immunitaires médiées par th17
US11103486B2 (en) 2011-05-19 2021-08-31 The Johns Hopkins University Treatment of autoimmune disorders and infections using antagonists of SGK1 activity

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