Interleukin-12 induces expression of interferon regulatory factor-1 via signal transducer and activator of transcription-4 in human T helper type 1 cells
Interleukin-12 induces expression of interferon regulatory factor-1 via signal transducer and activator of transcription-4 in human T helper type 1 cells
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DOI：
10.1074/jbc.274.10.6698
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发表时间：
1999-03-05
影响因子：
4.8
通讯作者：
Rogge, L
中科院分区：
文献类型：
--
作者：
Coccia, EM;Passini, N;Rogge, L
IRF-1基因缺陷小鼠在辅助性T细胞(Th1)发育过程中表现出明显缺陷。在本报告中，我们研究了IRF-1在人T辅助细胞分化过程中的表达。在已建立的Th1和Th2细胞中，IRF-1mRNA的表达没有显著差异，但白介素12(IL-12)诱导Th1细胞中IRF-1转录水平显著上调，而Th2细胞中IRF-1转录水平无明显上调。我们证明，IL-12诱导的IRF-1的上调是由信号转导和转录激活因子-4介导的，该信号转导和转录激活因子-4与存在于IRF-1基因启动子中的干扰素-γ激活序列结合。含有IRF-1干扰素-γ激活序列元件的报告基因构建体对IL-12的强烈依赖激活进一步证明了信号转导和转录激活因子-4在IL-12诱导的T细胞IRF-1转录上调中的关键作用。在通过T细胞受体刺激初始的CD4(+)T细胞后，IRF-1的表达被强烈地诱导，而与启动时存在的细胞因子无关，这表明该转录因子在启动Th1特异性转录级联反应中不起主要作用。然而，我们发现IRF-1是IL-12的靶基因，提示IL-12诱导的Th1细胞的某些效应功能可能是由IRF-1介导的。
IRF-1-deficient mice show a striking defect in the development of T helper 1 (Th1) cells. In the present report, we investigate the expression of IRF-1 during differentiation of human T helper cells. No significant differences of IRF-1 mRNA expression were found in established Th1 and Th2 cells; however, interleukin 12 (IL-12) induced a strong up-regulation of IRF-1 transcripts in Th1 but not in Th2 cells. We demonstrate that IL-12-induced up-regulation of IRF-1 is mediated by signal transducer and activator of transcription-4, which binds to the interferon (IFN)-gamma-activated sequence present in the promoter of the IRF-1 gene. Strong IL-12-dependent activation of a reporter gene construct containing the IRF-1 IFN-gamma-activated sequence element provides further evidence for the key role of signal transducer and activator of transcription-4 in the IL-12-induced up-regulation of IRF-1 transcripts in T cells. IRF-1 expression was strongly induced after stimulation of naive CD4(+) T cells via the T cell receptor, irrespective of the cytokines present at priming, indicating that this transcription factor does not play a major role in initiating a Th1-specific transcriptional cascade in differentiating helper T cells. However, our finding that IRF-1 is a target gene of IL-12 suggests that some of the IL-12-induced effector functions of Th1 cells may be mediated by IRF-1.