COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis.

Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar A, Marnett LJ, Bright JJ
J Clin Immunol. 2006 26 (1): 73-85

PMID: 16418805 · DOI:10.1007/s10875-006-8787-y

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 mug 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.

MeSH Terms (20)

Animals Cell Proliferation Cyclooxygenase 2 Inhibitors Demyelinating Diseases Encephalomyelitis, Autoimmune, Experimental Inflammation Interferon-gamma Interleukin-12 Janus Kinase 2 Mice Mice, Inbred C57BL Multiple Sclerosis, Chronic Progressive Multiple Sclerosis, Relapsing-Remitting Phosphorylation Protein-Tyrosine Kinases Proto-Oncogene Proteins Signal Transduction STAT3 Transcription Factor STAT4 Transcription Factor Th1 Cells

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