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IL-27 induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways
被引:94
作者:
Owaki, Toshiyuki
Asakawa, Masayuki
Fukai, Fumio
Mizuguchi, Junichiro
Yoshimoto, Takayuki
机构:
[1] Tokyo Med Univ, Intractable Immune Syst Dis Res Ctr, Shinjuku Ku, Tokyo 1608402, Japan
[2] Tokyo Univ Sci, Dept Patho Physiol, Fac Pharmaceut Sci, Chiba, Japan
[3] Tokyo Med Univ, Dept Immunol, Tokyo, Japan
关键词:
D O I:
10.4049/jimmunol.177.11.7579
中图分类号:
R392 [医学免疫学];
Q939.91 [免疫学];
学科分类号:
100102 ;
摘要:
IL-27, a novel member of the IL-6/IL-12 family, activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130 subunits, resulting in positive and negative regulations of immune responses. We recently demonstrated that IL-27 induces Th1 differentiation through ICAM-1/LFA-1 interaction in a STAT1-dependent, but T-bet-independent mechanism. In this study, we further investigated the molecular mechanisms by focusing on p38 MAPK and ERK1/2. IL-27-induced Th1 differentiation was partially inhibited by lack of T-bet expression or by blocking ICAM-1ALFA-1 interaction with anti-ICAM-1 and/or anti-LFA-1, and further inhibited by both. Similarly, the p38 MAPK inhibitor, SB203580, or the inhibitor of ERK1/2 phosphorylation, PD98059, partially suppressed IL-27-induced Th1 differentiation and the combined treatment completely suppressed it. p38 MAPK was then revealed to be located upstream of T-bet,. and SB203580, but not PD98059, inhibited T-bet-dependent Thl differentiation. In contrast, ERK1/2 was shown to be located downstream of ICAM-1LFA-1, and PD98059, but not SB203580, inhibited ICAM-1/LFA-1-dependent Thl differentiation. Furthermore, it was demonstrated that STAT1 is important for IL-27-induced activation of ERK1/2, but not p38 MAPK, and that IL-27 directly induces mRNA expression of growth arrest and DNA damage-inducible 45 gamma, which is known to mediate activation of p38 MAPK. Finally, IL-12R beta 2 expression was shown to be up-regulated by IL-27 in both T-bet- and ICAM-1/LFA-1-dependent mechanisms. Taken together, these results suggest that IL-27 induces Thl differentiation via two distinct pathways, p38 MAPK/T-bet- and ICAM-1/LFA-1/ERKI/2-dependent pathways. This is in contrast to IL-12, which induces it via only p38 MAPK/T-bet-dependent pathway. The Journal of Immunology, 2006, 177: 7579-7587.
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页码:7579 / 7587
页数:9
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