IRF4 regulates IL-10 gene expression in CD4+ T cells through differential nuclear translocation
IRF4 regulates IL-10 gene expression in CD4+ T cells through differential nuclear translocation
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DOI：
10.1016/j.cellimm.2011.02.008
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发表时间：
2011-01-01
影响因子：
4.3
通讯作者：
Im, Sin-Hyeog
中科院分区：
文献类型：
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作者：
Lee, Choong-Gu;Hwang, Won;Im, Sin-Hyeog
CD 4（+）T细胞在产生针对多种病原体的保护性免疫中起关键作用。主要的两种类型的效应CD 4（+）T细胞，Th 1和Th 2的特征在于它们产生标志性细胞因子的能力。其中，IL-10是一种多功能细胞因子，在维持免疫和耐受之间的平衡中起着至关重要的作用。虽然IL-10由分化的原代Th 1和Th 2细胞产生，但Th 2细胞在刺激后产生高得多的IL-10水平。然而，在转录水平上的IL-10基因调控的分子机制的信息很少。干扰素调节因子IRF 4是IRF家族转录因子的成员，在CD 4（+）T细胞向Th 2细胞的发育中起关键作用。在本研究中，我们阐明了IRF 4介导的IL-10基因在原代CD 4（+）T细胞中转录的潜在机制。IRF 4与IL-10基因座中的IRF 4应答元件的Th 2特异性结合增强了Th 2细胞中的IL-10表达。通过siRNA敲低IRF 4降低Th 2细胞中IL-10的表达水平。在刺激后，Th 2细胞中IRF 4的核转位要高得多，这有助于维持Th 2细胞的IL-10（高）表型。总的来说，我们的研究结果表明，刺激驱动的IRF 4在细胞核中的数量差异及其与IL-10调控元件的结合是诱导IL-10（高）基因在Th 2细胞中表达的关键机制。(C)2011 Elsevier Inc. All rights reserved.
CD4(+) T cells play critical roles in the generation of protective immunity against a variety of pathogens. The main two types of effector CD4(+) T cells, Th1 and Th2 are characterized by their ability to produce signature cytokines. Among them, IL-10 is a multi-functional cytokine that plays a crucial role in maintaining the balance between immunity and tolerance. Although IL-10 is produced by both differentiated primary Th1 and Th2 cells, Th2 cells produce much higher levels of IL-10 upon stimulation. However, little information is available on the molecular mechanisms of IL-10 gene regulation at the transcriptional level. Interferon regulatory factor IRF4 is a member of the IRF family of transcription factors and plays critical roles in the development of CD4(+) T cells into Th2 cells. In this present study, we elucidate the underlying mechanism of IRF4 mediated IL-10 gene transcription in primary CD4(+) T cells. Th2 specific binding of IRF4 to the IRF4 responsive elements in IL-10 locus potentiated IL-10 expression in Th2 cells. Knockdown of IRF4 by siRNA decreased IL-10 expression level in Th2 cells. Nuclear translocation of IRF4 was much higher in Th2 cells upon stimulation, which contribute to maintain IL-10(high) phenotype of Th2 cells. Collectively, our results suggest that stimulation driven quantitative differences of IRF4 in the nucleus and its binding to IL-10 regulatory elements are crucial mechanisms to induce IL-10(high) gene expression in Th2 cells. (C) 2011 Elsevier Inc. All rights reserved.