Mechanism for p38 alpha-mediated Experimental Autoimmune Encephalomyelitis

作者：Namiki Kana; Matsunaga Hirofumi; Yoshioka Kento; Tanaka Kensuke; Murata Kazuya; Ishida Junji; Sakairi Akira; Kim Jundal; Tokuhara Naoki; Shibakawa Nobuhiko; Shimizu Motohisa; Wada Yukinori; Tokunaga Yasunori; Shigetomi Manabu; Hagihara Masahiko; Kimura Sadao; Sudo Tatsuhiko; Fukamizu Akiyoshi; Kasuya Yoshitoshi^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(29): 24228-24238.

DOI：10.1074/jbc.M111.338541

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 alpha in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38 alpha(+/-) mice (p38 alpha(-/-) 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 alpha(+/-) 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 alpha 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 alpha 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 alpha participates in the pathogenesis of EAE through IL-17 induction.

• 出版日期2012-7-13