IL-27 suppresses CD28-medicated IL-2 production through suppressor of cytokine signaling 3
IL-27 suppresses CD28-medicated IL-2 production through suppressor of cytokine signaling 3
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IL-27 通过细胞因子信号转导抑制因子 3 抑制 CD28 介导的 IL-2 生成
DOI：
10.4049/jimmunol.176.5.2773
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发表时间：
2006-03-01
影响因子：
4.4
通讯作者：
Yoshimoto, Takayuki
中科院分区：
文献类型：
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作者：
Owaki, Toshiyuki;Asakawa, Masayuki;Yoshimoto, Takayuki
IL-27是一种新的IL-6/IL-12家族细胞因子，不仅在Th 1分化的早期调节中发挥作用，而且对免疫应答发挥抑制作用，包括抑制促炎细胞因子的产生。然而，IL-27发挥抑制作用的分子机制仍不清楚。在这项研究中，我们证明了IL-27抑制CD 28介导的IL-2的产生，细胞因子信号转导抑制因子3（SOCS 3）在抑制作用中起着关键作用。尽管IL-27在IL-12存在下增强了用板包被的抗CD 3和抗CD 28刺激的初始CD 4（+）T细胞的IFN-γ产生，但EL-27同时抑制了CD 28介导的IL-2产生。与抑制相关，IL-27显示增加SOCS 3表达。使用缺乏信号分子的各种小鼠的分析显示，IL-2产生的抑制依赖于STAT 1，但不依赖于STAT 3、STAT 4和T-bet，并且与SOCS 3表达的诱导高度相关。在T细胞杂交瘤细胞系2B 4中观察到IL-27对CD 28介导的IL-2产生的类似抑制和对SOCS 3表达的增强。在T细胞系中强制表达反义SOCS 3或显性负性SOCS 3可阻断IL-27诱导的对CD 28介导的IL-2产生的抑制。此外，IL-27预处理抑制IL-2介导的细胞增殖和STAT 5活化，尽管IL-27几乎不影响CD 25表达的诱导水平。这些结果表明，IL-27抑制CD 28介导的IL-2产生以及IL-2应答，并且由IL-27诱导表达的SOCS 3在负反馈机制中的抑制作用中起关键作用。
IL-27 is a novel IL-6/IL-12 family cytokine that not only plays a role in the early regulation of Th1 differentiation, but also exerts an inhibitory effect on immune responses, including the suppression of proinflammatory cytokine production. However, the molecular mechanism by which IL-27 exerts the inhibitory effect remains unclear. In this study we demonstrate that IL-27 inhibits CD28-mediated IL-2 production and that suppressor of cytokine signaling 3 (SOCS3) plays a critical role in the inhibitory effect. Although IL-27 enhanced IFN-gamma production from naive CD4(+) T cells stimulated with plate-coated anti-CD3 and anti-CD28 in the presence of IL-12, EL-27 simultaneously inhibited CD28-mediated IL-2 production. Correlated with the inhibition, IL-27 was shown to augment SOCS3 expression. Analyses using various mice lacking a signaling molecule revealed that the inhibition of IL-2 production was dependent on STAT1, but not on STAT3, STAT4, and T-bet, and was highly correlated with the induction of SOCS3 expression. Similar inhibition of CD28-mediated IL-2 production and augmentation of SOCS3 expression by IL-27 were observed in a T cell hybridoma cell line, 2B4. Forced expression of antisense SOCS3 or dominant negative SOCS3 in the T cell line blocked the IL-27-inudced inhibition of CD28-mediated IL-2 production. Furthermore, pretreatment with IL-27 inhibited IL-2-mediated cell proliferation and STAT5 activation, although IL-27 hardly affected the induction level of CD25 expression. These results suggest that IL-27 inhibits CD28-mediated IL-2 production and also IL-2 responses, and that SOCS3, whose expression is induced by IL-27, plays a critical role in the inhibitory effect in a negative feedback mechanism.