The forkhead transcription factor FoxO regulates transcription of p27Kip1 and bim in response to IL-2
The forkhead transcription factor FoxO regulates transcription of p27Kip1 and bim in response to IL-2
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DOI：
10.4049/jimmunol.168.10.5024
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发表时间：
2002-05-15
影响因子：
4.4
通讯作者：
Medema, RH
中科院分区：
文献类型：
--
作者：
Stahl, M;Dijkers, PF;Medema, RH
细胞因子白细胞介素 - 2（IL - 2）在活化T细胞的增殖和存活中起着非常重要的作用。IL - 2的这些作用依赖于通过磷脂酰肌醇3 - 激酶（PI3K）途径的信号传导。我们及其他研究人员已经表明，PI3K通过激活蛋白激酶B / Akt，抑制了许多叉头转录因子（FoxO1、FoxO3和FoxO4）的转录激活。在本研究中，我们研究了这些叉头转录因子在IL - 2诱导的T细胞增殖和存活中的作用。我们发现IL - 2以PI3K依赖的方式调节FoxO3的磷酸化。FoxO3的磷酸化和失活似乎在IL - 2介导的T细胞存活中起重要作用，因为仅仅激活FoxO3就足以引发T细胞凋亡。实际上，活化的FoxO3能够诱导IL - 2调节基因的表达，例如细胞周期蛋白依赖性激酶抑制剂P27（KiP1）和促凋亡的Bcl - 2家族成员Bim。此外，我们发现IL - 2在原代T细胞中触发了一种快速的、PI3K依赖的FoxO1a磷酸化。因此，我们提出IL - 2使FoxO转录因子失活在T细胞增殖和存活中起着关键作用。
The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) path ay. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits transcriptional activation by a number of forkhead transcription factors (FoxO1, FoxO3, and FoxO4). In this study we have investigated the role of these forkhead transcription factors in the IL-2-induced T cell proliferation and survival. We show that IL-2 regulates phosphorylation of FoxO3 in a PI3K-dependent fashion. Phosphorylation and inactivation of FoxO3 appears to play an important role in IL-2-mediated T cell survival, because mere activation of FoxO3 is sufficient to trigger apoptosis in T cells. Indeed, active FoxO3 can induce expression of IL-2-regulated genes, such as the cdk-inhibitor P27(KiP1) and the proapoptotic Bcl-2 family member Bim. Furthermore, we show that IL-2 triggers a rapid, PI3K-dependent, phosphorylation of FoxO1a in primary T cells. Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival.