STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production
STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production
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DOI：
10.4049/jimmunol.180.5.2903
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Yoshimoto, Takayuki
中科院分区：
文献类型：
--
作者：
Owaki, Toshiyuki;Asakawa, Masayuki;Yoshimoto, Takayuki
IL-27是IL-6/IL-12家族的成员，通过其受体激活STAT 1和STAT 3，其由WSX-1和gp 130亚基组成，导致Th 1分化的增强和促炎细胞因子产生的抑制。在本研究中，我们研究了STAT 3在IL-27介导的免疫功能中的作用。IL-27在野生型幼稚CD 4（+）T细胞中诱导STAT 1、-2、-3和-5的磷酸化，但在STAT 3缺陷队列中不能诱导STAT 3和STAT 5的磷酸化。IL-27不仅诱导促炎反应，包括上调ICAM-1、T细胞中表达的T-box以及IL-12 R β 2和Th 1分化，而且诱导抗炎反应，包括抑制促炎细胞因子产生，例如IL-2、IL-4和IL-13，即使在STAT 3缺陷的初始CD 4（+）T细胞中。相比之下，IL-27增加了野生型幼稚CD 4（+）T细胞中c-Myc和Pim-1的表达并诱导细胞增殖，但在STAT 3缺陷的队列中没有。此外，IL-27不能激活STAT 3，增加c-Myc和Pim-1的表达，并诱导表达突变gp 130的pro-B BaF/3转染子中的细胞增殖，其中胞质区域的YXXQ基序中的推定的STAT 3结合的四个Tyr残基被Phe取代。这些结果表明，STAT 3通过gp 130被IL-27激活，并且是IL-27介导的细胞增殖所必需的，但不是IL-27诱导的Th 1分化和抑制促炎细胞因子产生所必需的。因此，IL-27可能是一种细胞因子，其分别通过不同的受体亚基WSX-1和gp 130激活STAT 1和STAT 3，以介导其个体免疫功能。
IL-27, a 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 augmentation of Th1 differentiation and suppression of proinflammatory cytokine production. In the present study, we investigated the role of STAT3 in the IL-27-mediated immune functions. IL-27 induced phosphorylation of STAT1, -2, -3 and -5 in wild-type naive CD4(+) T cells, but failed to induce that of STAT3 and STAT5 in STAT3-deficient cohorts. IL-27 induced not only proinflammatory responses including up-regulation of ICAM-1, T-box expressed in T cells, and IL-12R beta 2 and Th1 differentiation, but also anti-inflammatory responses including suppression of proinflammatory cytokine production such as IL-2, IL-4, and IL-13 even in STAT3-deficient naive CD4(+) T cells. In contrast, IL-27 augmented c-Myc and Pim-1 expression and induced cell proliferation in wild-type naive CD4(+) T cells but not in STAT3-deficient cohorts. Moreover, IL-27 failed to activate STAT3, augment c-Myc and Pim-1 expression, and induce cell proliferation in pro-B BaF/3 transfectants expressing mutant gp130, in which the putative STAT3-binding four Tyr residues in the YXXQ motif of the cytoplasmic region was replaced by Phe. These results suggest that STAT3 is activated through gp130 by IL-27 and is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. Thus, IL-27 may be a cytokine, which activates both STAT1 and STAT3 through distinct receptor subunits, WSX-1 and gp130, respectively, to mediate its individual immune functions.