Motohisa Shimizu

Mechanism for p38α-mediated experimental autoimmune encephalomyelitis

Background: p38 signaling pathway plays a key role in inflammatory diseases. Results: A single copy disruption of the p38α gene or a p38α inhibitor markedly reduced the pathogenesis of EAE by decreasing IL-17 production. Conclusion: p38α regulates the pathogenesis of EAE through transcriptional regulation of IL-17 production. Significance: Anti-p38α strategy achieves therapeutic benefit for the treatment of multiple sclerosis. 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 p38α in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38α+/− mice (p38α−/− 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 p38α+/− 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 p38α 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 p38α 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 p38α participates in the pathogenesis of EAE through IL-17 induction.