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COX-2 Inhibitors Modulate IL-12 Signaling Through JAK-STAT Pathway Leading to Th1 Response in Experimental Allergic Encephalomyelitis

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Abstract

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). IL-12 plays a crucial role in the pathogenesis of EAE/MS and inhibition of IL-12 production or IL-12 signaling was effective in preventing EAE. Cyclooxygenase (COX-2) is a key enzyme promoting inflammation in rheumatoid arthritis and tumor induced angiogenesis. Recent studies have shown that COX-2 inhibitors prevent EAE, however, their mechanism of action is not fully understood. In this study, we show that in vivo treatment (i.p.) with 100 μg COX-2 selective inhibitors (LM01, LM08, LM11, and NS398), on every other day from day 0 to 30, significantly reduced the incidence and severity of EAE in SJL/J and C57BL/6 mice. Further analyses showed that the COX-2 inhibitors reduced neural antigen-induced IL-12 production, T cell proliferation and Th1 differentiation ex vivo and in vitro. The COX-2 inhibitors also decreased IL-12-induced T cell responses through blocking tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 proteins in T cells. These results demonstrate that COX-2 inhibitors ameliorate EAE in association with the modulation of IL-12 signaling through JAK-STAT pathway leading to Th1 differentiation and suggest their use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.

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References

  1. Martin R, McFarland HF, McFarlin DE: Immunology of demyelinating disease. Ann Rev Immunol 10:153–169, 1992

    Article  CAS  Google Scholar 

  2. Dean G: How many people in the world have MS? Neuroepidemiology 13:1–7, 1994

    CAS  PubMed  Google Scholar 

  3. Sayetta RB: Theories of the etiology of multiple sclerosis: A critical review. J Clin Lab Immunol 21:55–70, 1986

    CAS  PubMed  Google Scholar 

  4. Steinman LR, Martin C, Bernard P, Conlon, Oksenberg JR: Multiple sclerosis: Deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci 25:491–505, 2002

    Article  CAS  PubMed  Google Scholar 

  5. Donoghue S, Greenlees C: Drugs in development for the treatment of multiple sclerosis: Antigen non-Specific therapies, an update. Expert Opin Investig Drugs 9:167–171, 2000

    Article  CAS  PubMed  Google Scholar 

  6. Clegg A, Bryant J: Immunomodulatory drugs for multiple sclerosis: A systematic review of clinical and cost effectiveness. Expert Opin Pharmacother 2:623–639, 2001

    Article  CAS  PubMed  Google Scholar 

  7. Gold R, Hartung HP, Toyka KV: Animal models for autoimmune demyelinating disorders of the nervous system. Mol Med Today 6:88–91, 2000

    CAS  PubMed  Google Scholar 

  8. Bright JJ, Musuro, BF, Du C, Sriram S: Expression of IL-12 in CNS and lymphoid organs of mice with experimental allergic encephalomyelitis. J Neuroimmunol 82:22–30, 1998

    Article  CAS  PubMed  Google Scholar 

  9. Bright JJ, Du C, Coon M, Sriram S, Klaus SJ: Prevention of experimental allergic encephalomyelitis via inhibition of IL-12 signaling and IL-12-mediated Th1 differentiation: An effect of the novel anti-inflammatory drug lisofylline. J Immunol 161:7015–7022, 1998

    CAS  PubMed  Google Scholar 

  10. Bright JJ, Rodriguez M, Sriram S: Differential influence of interleukin-12 in the pathogenesis of autoimmune and virus-induced CNS demyelination. J Virol 73:1637–1639, 1999

    CAS  PubMed  Google Scholar 

  11. Bright JJ, Du C, Sriram S: Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol 162:6255–6262, 1999

    CAS  PubMed  Google Scholar 

  12. Natarajan C, Bright JJ: Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun 3:59–70, 2002

    Article  CAS  PubMed  Google Scholar 

  13. Natarajan C, Bright JJ: Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T cells and differentiation of neural antigen specific Th1 cells. J Immunol 169:6506–6513, 2002

    Google Scholar 

  14. Muthian G, Bright JJ: Quercetin ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T lymphocyte. J Clin Immunol 24:541–551, 2003

    Google Scholar 

  15. Brosnan CF, Raine CS: Mechanisms of immune injury in multiple sclerosis. Brain Pathol 6:243–257, 1996

    CAS  PubMed  Google Scholar 

  16. Bradl M, Linington C: Animal models of demyelination. Brain Pathol 6:303–311, 1996

    CAS  PubMed  Google Scholar 

  17. Trinchieri G: IL-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen specific adaptive immunity. Ann Rev Immunol 13:251–276, 1995

    CAS  Google Scholar 

  18. Trembleau ST, Germann MK, Gately Adorini L: The role of IL-12 in the induction of organ-specific autoimmune diseases. Immunol Today 16:383–386, 1995

    Article  CAS  PubMed  Google Scholar 

  19. Nicoletti F, Patti F, Cocuzza C, Zaccone P, Nicoletti A, Marco Di R, Reggio A: Elevated Serum levels of IL-12 in chronic progressive multiple sclerosis. J Neuroimmunol 70:87–90, 1996

    Article  CAS  PubMed  Google Scholar 

  20. Balashov KE, Smith DR, Khoury SJ, Hafler DA, Weiner HL: Increased IL-12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. Proc Natl Acad Sci USA. 94:599–603, 1997

    Article  CAS  PubMed  Google Scholar 

  21. Pagenstecher A, Lassmann S, Carson MJ, Kincaid CL, Stalde AK, Campbell IL: Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis. J Immunol 164:4481–4492, 2002

    Google Scholar 

  22. Leonard JP, Waldburger KE, Goldman SJ: Prevention of EAE by antibodies against interleukin-12. J Exp Med 181:381–385, 1995

    Article  CAS  PubMed  Google Scholar 

  23. Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM: Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol 15:5258–5267, 1995

    CAS  PubMed  Google Scholar 

  24. Darnell JE Jr, Kerr IM, Stark GR: JAK-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421, 1994

    CAS  PubMed  Google Scholar 

  25. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE Jr., Murphy KM : Interleukin-12 signaling in Th1 cells involves tyrosine phosphorylation of Stat3 and Stat4. J Exp Med 181:1755–1762, 1995

    Article  CAS  PubMed  Google Scholar 

  26. Bacon CM, EM Petricoin 3rd, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ: Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA. 92:7307–7311, 1995

    CAS  PubMed  Google Scholar 

  27. Liblau RS, Singer SM, McDevitt HO: Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 16:34–38, 1995

    CAS  PubMed  Google Scholar 

  28. Conboy IM, DeKruyff RH, Tate KM, Cao ZA, Moore TA, Umetsu DT, Jones PP: Novel genetic regulation of T helper 1 (Th1)/Th2 cytokine production and encephalitogenicity in inbred mouse strains. J Exp Med 185:439–451, 1997

    Article  CAS  PubMed  Google Scholar 

  29. Segal BM, Dwyer BK, Shevach EM: An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187:537–546, 1998

    Article  CAS  PubMed  Google Scholar 

  30. Vane JR, Bakhle YS, Botting RM: Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 38:97–120, 1998

    Article  CAS  PubMed  Google Scholar 

  31. Seibert K, Masferrer J, Zhang Y, Gregory S, Olson G, Hauser S, Leahy K, Perkins W, Isakson P: Mediation of inflammation by cyclooxygenase-2. Agents Actions Suppl 46:41–50, 1995

    CAS  PubMed  Google Scholar 

  32. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, VanDePutte LBA, Lipsky PE: Cyclooxygenase in biology and disease. FASEB J 12:1063–1073, 1998

    CAS  PubMed  Google Scholar 

  33. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716, 1998

    Article  CAS  PubMed  Google Scholar 

  34. Lipsky PE, Isakson PC: Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol 24: 9–14, 1997

    Google Scholar 

  35. Misko TP, Trotter JL, Cross AH: Mediation of inflammation by encephalitogenic cells: IFN, iNOS and COX-2. J Neuroimmunol 61:195–204, 1995

    Article  CAS  PubMed  Google Scholar 

  36. Fretland DJ: Potential role of prostaglandins and Leukotrienes in multiple sclerosis and experimental allergic encephalomyelitis. Protaglandins Leukot. Essent. Fatty Acids 45:249–257, 1992

    CAS  Google Scholar 

  37. Miyamoto K, Oka N, Kawasaki T, Satoi H, Akiguchi I, Kimura J: The effect of cyclooxygenase-2 inhibitor on experimental allergic neuritis. Neuroreport 9:2331–2334, 1998

    CAS  PubMed  Google Scholar 

  38. Moon C, Ahn M, Jee Y, Heo S, Kim S, Kim H, Sim KB, Koh CS, Shin YG, Shin T: Sodium salicylate-induced amelioration of experimental autoimmune encephalomyelitis in Lewis rats is associated with the suppression of inducible nitric oxide synthase and cyclooxygenases. Neurosci Lett. 12;356:123–126, 2004

    Google Scholar 

  39. Bright JJ, Kerr LD, Sriram S: TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of JAK1 and STAT5 in T lymphocytes. J Immunol 159:175–183, 1997

    CAS  PubMed  Google Scholar 

  40. Bright JJ, Sriram S: TGF-beta inhibits IL-12-induced activation of JAK-STAT pathway in T lymphocytes. J Immunol 161:1772–1777, 1998

    CAS  PubMed  Google Scholar 

  41. Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP, Marnett LJ: Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA 97:925–930, 2000

    Article  CAS  PubMed  Google Scholar 

  42. Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, Marnett LJ: Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. J Med Chem 43:2860–2870, 2000

    Article  CAS  PubMed  Google Scholar 

  43. Marnett LJ, Kalgulkar AS: Design of selective inhibitors of cyclooxygenase-2 as nonnuclcerogenic anti-inflammatory agents. Curr opin Chem Biol 2: 482– 490, 1998

    Article  CAS  PubMed  Google Scholar 

  44. Marnett LJ: Forum:reactive species of peroxynitrite. Chem Res Toxicol 11: 709, 1998

    CAS  PubMed  Google Scholar 

  45. Marnett LJ, Kalgutkar AS: Cyclooxygenase 2 inhibitors: Discovery, selectivity and the future. Trends Pharmacol Sci 20:465–469, 1999

    Article  CAS  PubMed  Google Scholar 

  46. Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA: Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 274:22903–22906, 1999

    Article  CAS  PubMed  Google Scholar 

  47. Crabtree GR: Contingent genetic regulatory events in T lymphocyte activation. Science 243:355–357, 1989

    CAS  PubMed  Google Scholar 

  48. Gately MK, Desai BB, Wolitzky AG, Quinn PM, Dwyer CM, Podlaski FJ, Familletti PC, Sinigaglia F, Chizonnite R, Gubler U: Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 147:874–882, 1991

    CAS  PubMed  Google Scholar 

  49. Bertagnolli MM, Lin BY, Young D, Herrmann SH: IL-12 augments antigen-dependent proliferation of activated T lymphocytes. J Immunol 149:3778–3783, 1992

    CAS  PubMed  Google Scholar 

  50. Yanagida T, Kato T, Igarashi O, Inoue T, Nariuchi H: Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone. J Immunol 152:4919–4928, 1994

    CAS  PubMed  Google Scholar 

  51. Kennedy MK, Picha KS, Shanebeck KD, Anderson DM, Grabstein KH: Interleukin-12 regulates the proliferation of Th1, but not Th2 or Th0, clones. Eur J Immunol 24:2271–2278, 1994

    CAS  PubMed  Google Scholar 

  52. Thierfelder WE, van DeursenJM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN: Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174,1996

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee

    Gladson Muthian, Himanshu P. Raikwar, Caroline Johnson, Johnson Rajasingh, Lawrence J. Marnett & John J. Bright

  2. Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee

    Amit Kalgutkar

  3. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee

    John J. Bright

  4. Methodist Research Institute, Clarian Health, 1800 N Capital Avenue, Suite E 504 C, Indianapolis, Indiana, 46202

    John J. Bright

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  1. Gladson Muthian
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  2. Himanshu P. Raikwar
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  3. Caroline Johnson
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  5. Amit Kalgutkar
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  7. John J. Bright
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Correspondence to John J. Bright.

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Muthian, G., Raikwar, H.P., Johnson, C. et al. COX-2 Inhibitors Modulate IL-12 Signaling Through JAK-STAT Pathway Leading to Th1 Response in Experimental Allergic Encephalomyelitis. J Clin Immunol 26, 73–85 (2006). https://doi.org/10.1007/s10875-006-8787-y

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  • DOI: https://doi.org/10.1007/s10875-006-8787-y

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