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.
引用
收藏
页码:7579 / 7587
页数:9
相关论文
共 41 条
[1]   T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells [J].
Afkarian, M ;
Sedy, JR ;
Yang, J ;
Jacobson, NG ;
Cereb, N ;
Yang, SY ;
Murphy, TL ;
Murphy, KM .
NATURE IMMUNOLOGY, 2002, 3 (06) :549-557
[2]   Cutting edge:: Early IL-4 production governs the requirement for IL-27-WSX-1 signaling in the development of protective Th1 cytokine responses following Leishmania major infection [J].
Artis, D ;
Johnson, LM ;
Joyce, K ;
Saris, C ;
Villarino, A ;
Hunter, CA ;
Scott, P .
JOURNAL OF IMMUNOLOGY, 2004, 172 (08) :4672-4675
[3]   Development of Th1-type immune responses requires the type I cytokine receptor TCCR [J].
Chen, Q ;
Ghilardi, N ;
Wang, H ;
Baker, T ;
Xie, MH ;
Gurney, A ;
Grewal, IS ;
de Sauvage, FJ .
NATURE, 2000, 407 (6806) :916-920
[4]   GADD45β/GADD45γ and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNγ production in T cells [J].
Chi, HB ;
Lu, BF ;
Takekawa, M ;
Davis, RJ ;
Flavell, RA .
EMBO JOURNAL, 2004, 23 (07) :1576-1586
[5]   Interleukin-10 and the regulation of mitogen-activated protein kinases:: are these signalling modules targets for the anti-inflammatory action of this cytokine? [J].
Haddad, JJ ;
Saadé, NE ;
Safieh-Garabedian, B .
CELLULAR SIGNALLING, 2003, 15 (03) :255-267
[6]   Principles of interleukin (IL)-6-type cytokine signalling and its regulation [J].
Heinrich, PC ;
Behrmann, I ;
Haan, S ;
Hermanns, HM ;
Müller-Newen, G ;
Schaper, F .
BIOCHEMICAL JOURNAL, 2003, 374 (01) :1-20
[7]   IL-27 and IFN-α signal via Stat1 and Stat3 and induce T-Bet and IL-12Rβ2 in naive T cells [J].
Hibbert, L ;
Pflanz, S ;
Malefyt, RD ;
Kastelein, RA .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2003, 23 (09) :513-522
[8]   New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions [J].
Hunter, CA .
NATURE REVIEWS IMMUNOLOGY, 2005, 5 (07) :521-531
[9]   An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells [J].
Kamiya, S ;
Owaki, T ;
Morishima, N ;
Fukai, F ;
Mizuguchi, J ;
Yoshimoto, T .
JOURNAL OF IMMUNOLOGY, 2004, 173 (06) :3871-3877
[10]   Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice [J].
Kaplan, MH ;
Sun, YL ;
Hoey, T ;
Grusby, MJ .
NATURE, 1996, 382 (6587) :174-177