Mechanism for p38α-mediated experimental autoimmune encephalomyelitis.
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.
Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Kana
K
Namiki
Hirofumi
H
Matsunaga
Kento
K
Yoshioka
Kensuke
K
Tanaka
Kazuya
K
Murata
Junji
J
Ishida
Akira
A
Sakairi
Jundal
J
Kim
Naoki
N
Tokuhara
Nobuhiko
N
Shibakawa
Motohisa
M
Shimizu
Yukinori
Y
Wada
Yasunori
Y
Tokunaga
Manabu
M
Shigetomi
Masahiko
M
Hagihara
Sadao
S
Kimura
Tatsuhiko
T
Sudo
Akiyoshi
A
Fukamizu
Yoshitoshi
Y
Kasuya
D000818:Animals; D024202:Electrophoretic Mobility Shift Assay; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020871:RNA Stability / Q000235:genetics
D004791:Enzyme Inhibitors; D020381:Interleukin-17; D048308:Mitogen-Activated Protein Kinase 14