IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling.
IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling.
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DOI：
10.4049/jimmunol.1302246
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发表时间：
2015-11-01
期刊：
影响因子：
--
通讯作者：
Pot C
中科院分区：
文献类型：
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作者：
Peters A;Fowler KD;Chalmin F;Merkler D;Kuchroo VK;Pot C
已知Th 17细胞的分化通过STAT 3的活化而被促进，通过STAT 1的活化而被抑制。尽管两种转录因子都被包括IL-6、IL-21和IL-27在内的几种细胞因子激活，但这些细胞因子中的每一种对Th 17分化具有非常不同的作用，范围从强诱导（IL-6）到强抑制（IL-27）。为了确定这些差异的分子基础，我们测量了IL-6、IL-21和IL-27以及细胞因子对随时间的STAT 3和STAT 1激活曲线。我们发现，活化的STAT 3与活化的STAT 1的比率在确定细胞因子是否促进或抑制Th 17分化中至关重要。因此，IL-6和IL-21诱导pSTAT 3：pSTAT 1比率大于1，导致促进Th 17分化，而IL-27或IL-6+ IL-27诱导pSTAT 3：pSTAT 1比率低于1，导致抑制Th 17分化。与这些发现一致，我们表明IL-27诱导足够的pSTAT 3，以促进在STAT 1的情况下Th 17分化。此外，IL-27诱导的STAT 1缺陷型T细胞与真正的高度促炎性Th 17细胞无法区分，因为它们在过继转移后诱导严重的实验性自身免疫性脑脊髓炎（EAE）。我们的研究结果表明，由细胞因子或细胞因子对诱导的pSTAT 3：pSTAT 1的比率可用于预测它们是否诱导有能力的Th 17分化程序。
It is known that differentiation of Th17 cells is promoted by activation of STAT3 and inhibited by activation of STAT1. Although both transcription factors are activated by several cytokines including IL-6, IL-21 and IL-27, each of these cytokines has very different effects on Th17 differentiation ranging from strong induction (IL-6) to strong inhibition (IL-27). To determine the molecular basis for these differences, we measured STAT3 and STAT1 activation profiles for IL-6, IL-21, and IL-27, as well as for cytokine pairs over time. We found that the ratio of activated STAT3 to activated STAT1, is crucial in determining whether cytokines promote or inhibit Th17 differentiation. Thus, IL-6 and IL-21 induced pSTAT3:pSTAT1 ratios greater than one leading to promotion of Th17 differentiation, whereas IL-27 or IL-6+IL27 induced pSTAT3:pSTAT1 ratios below one resulting in inhibition of Th17 differentiation. Consistent with these findings, we show that IL-27 induces sufficient pSTAT3 to promote Th17 differentiation in the absence of STAT1. Furthermore, IL-27-induced STAT1-deficient T cells were indistinguishable from bona fide highly pro-inflammatory Th17 cells, as they induced severe experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. Our results suggest, that the ratio of pSTAT3:pSTAT1 induced by a cytokine or cytokine pairs can be used to predict whether or not they induce a competent Th17 differentiation program.