Regulation of the foxp3 Gene by the Th1 Cytokines: The Role of IL-27-Induced STAT1
Regulation of the foxp3 Gene by the Th1 Cytokines: The Role of IL-27-Induced STAT1
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DOI：
10.4049/jimmunol.182.2.1041
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发表时间：
2009-01-15
影响因子：
4.4
通讯作者：
Schmidt-Weber, Carsten B.
中科院分区：
文献类型：
--
作者：
Ouaked, Nadia;Mantel, Pierre-Yves;Schmidt-Weber, Carsten B.
在过敏性患者中已经报道了T调节细胞的功能活性受损，并且导致对自身免疫性疾病的易感性增加。T调节细胞分化的主要调节因子，转录因子FOXP 3，是它们的发育和功能所必需的。尽管它的关键作用，相对知之甚少的分子机制调控foxp 3基因的表达。在本研究中，在表观遗传和基因表达水平上分析了Th 1细胞因子对人T调节细胞分化的影响，并揭示了STAT 1激活细胞因子IL-27和IFN-γ放大TGF-β诱导的FOXP 3表达的机制。这项研究显示STAT 1结合元件内的近端部分的人FOXP 3启动子，我们以前假设作为一个关键的调控单位。IL-27刺激后STAT 1与FOXP 3启动子的直接结合增加了其反式激活过程，并在FOXP 3启动子的这一关键区域诱导了允许的组蛋白修饰，这表明IL-27通过两种机制促进FOXP 3表达。我们的数据证明了调节FOXP 3表达的分子机制，这对于开发旨在支持免疫系统抗炎机制的新药靶标具有相当大的意义。免疫学杂志，2009，182：1041-1049.
Impaired functional activity of T regulatory cells has been reported in allergic patients and results in an increased susceptibility to autoimmune diseases. The master regulator of T regulatory cell differentiation, the transcription factor FOXP3, is required for both their development and function. Despite its key role, relatively little is known about the molecular mechanisms regulating foxp3 gene expression. In the present study, the effect of Th1 cytokines on human T regulatory cell differentiation was analyzed at epigenetic and gene expression levels and reveals a mechanism by which the STAT1-activating cytokines IL-27 and IFN-gamma amplify TGF-beta-induced FOXP3 expression. This study shows STAT1 binding elements within the proximal part of the human FOXP3 promoter, which we previously hypothesized to function as a key regulatory unit. Direct binding of STAT1 to the FOXP3 promoter following IL-27 stimulation increases its transactivation process and induces permissive histone modifications in this key region of the FOXP3 promoter, suggesting that FOXP3 expression is promoted by IL-27 by two mechanisms. Our data demonstrate a molecular mechanism regulating FOXP3 expression, which is of considerable interest for the development of new drug targets aiming to support anti-inflammatory mechanisms of the immune system. The Journal of Immunology, 2009, 182: 1041-1049.