Journal of Clinical Immunology

, Volume 26, Issue 1, pp 73–85 | Cite as

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

  • Gladson Muthian
  • Himanshu P. Raikwar
  • Caroline Johnson
  • Johnson Rajasingh
  • Amit Kalgutkar
  • Lawrence J. Marnett
  • John J. Bright


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.


Autoimmunity EAE/MS Th1 cell cytokine signaling COX-2 


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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Gladson Muthian
    • 1
  • Himanshu P. Raikwar
    • 1
  • Caroline Johnson
    • 1
  • Johnson Rajasingh
    • 1
  • Amit Kalgutkar
    • 2
  • Lawrence J. Marnett
    • 1
  • John J. Bright
    • 1
    • 3
    • 4
  1. 1.Department of NeurologyVanderbilt University Medical CenterNashville
  2. 2.Department of BiochemistryVanderbilt University Medical CenterNashville
  3. 3.Department of PharmacologyVanderbilt University Medical CenterNashville
  4. 4.Methodist Research Institute, Clarian Health

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