T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6
T-cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6
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DOI：
10.1093/emboj/16.13.4007
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发表时间：
1997-07-01
期刊：
影响因子：
11.4
通讯作者：
Nakayama, T
中科院分区：
文献类型：
--
作者：
Kubo, M;Ransom, J;Nakayama, T
在外周CD 4（+）T淋巴细胞的发育过程中，细胞因子基因的差异表达，例如白细胞介素（IL）-2和IL-4的差异表达，发生在不同的T细胞亚群中，IL-4是由辅助性T细胞2（Th 2）产生的细胞因子，并且IL-4受体（IL-4 R）介导的信号传导途径被认为是定型为Th 2表型所需的。然而，开发Th亚群特异性产生IL-4的分子基础仍不清楚，我们在此证明IL-4启动子在正常情况下不形成IL-4转录物的Th 1和B细胞以及产生IL-4的T细胞中是有功能的，基于IL-4基因的几个不同上游和下游区域对IL-4启动子活性的影响的研究，在3 '非翻译区鉴定了Th 1特异性IL-4沉默元件，沉默子区域含有通常由IL-4 R信号传导途径STAT 6调节的转录因子的共有序列。STAT 6蛋白在Th 2细胞核中表达，但在Th 1细胞核中不表达。STAT 6结合位点的缺失和STAT 6功能的抑制导致了沉默功能的出现，即使在Th 2细胞中也是如此。这些结果提供了沉默元件和STAT 6与该元件的结合在决定定型为Th 2表型中起允许作用的证据。
During development of CD4(+) T lymphocytes in the periphery, differential expression of cytokine genes, such as those of interleukin (IL)-2 and IL-4, occurs in distinct T-cell subsets, IL-4 is a cytokine produced by T-helper 2 (Th2) cells, and the IL-4 receptor (IL-4R)-mediated signaling pathway is thought to be required for commitment to the Th2 phenotype, However, the molecular basis for development of the Th subset-specific production of IL-4 remains unclear, We demonstrate here that the IL-4 promoter is functional in Th1 and B cells which do not normally form IL-4 transcripts as well as in IL-4-producing T cells, Based on studies of the effect of several different upstream and downstream regions of the IL-4 gene on IL-4 promoter activity, a Th1-specific IL-4 silencer element was identified in the 3'-untranslated region, The silencer region contained a consensus sequence for a transcriptional factor that is normally regulated by the IL-4 R signaling pathway, STAT6. Nuclear expression of STAT6 protein, which was shown to bind to the silencer region, was observed in Th2 cells but not in Th1 cells, Deletion of the STAT6-binding site from the silencer region and inhibition of STAT6 function resulted in the appearance of silencing function even in Th2 cells. These results provide evidence that the silencer element, and the binding of STAT6 to this element, play a permissive role in determining the commitment into Th2 phenotype.