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Mechanism for p38-mediated experimental autoimmune encephalomyelitis

Namiki, K;Matsunaga, H;Yoshioka, K;Tanaka, K;Murata, K;Ishida, J;Sakairi, A;Kim, J;Tokuhara, N;Shibakawa, N;Shimizu, M;Wada, Y;Tokunaga, Y;Shigetomi, M;Hagihara, M;Kimura, S;Sudo, T;Fukamizu, A;Kasuya, Y;

One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses. In this study, we analyzed the roles of p38 in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38(+/-) mice (p38(-/-) showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC) from sensitized WT mice with MOG(35-55) to naive WT-induced EAE was much more severe compared with the case using LNC from sensitized p38(+/-) mice. Comprehensive analysis of cytokines from MOG(35-55)-challenged LNC by Western blot array revealed that production of IL-17 was significantly reduced by a single copy disruption of the p38 gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription of the Il17 gene. Furthermore, oral administration of a highly specific p38 inhibitor (UR-5269) to WT mice at the onset of EAE markedly suppressed the progression of EAE compared with a vehicle group. These results suggest that p38 participates in the pathogenesis of EAE through IL-17 induction.