IL-4-activated STAT-6 inhibits IFN-gamma-induced CD40 gene expression in macrophages/microglia.
IL-4-activated STAT-6 inhibits IFN-gamma-induced CD40 gene expression in macrophages/microglia.
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DOI：
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发表时间：
2000
影响因子：
4.4
通讯作者：
V. Nguyen;E. Benveniste
中科院分区：
文献类型：
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作者：
V. Nguyen;E. Benveniste
细胞因子IFN-γ和IL-4之间的拮抗作用已被充分证明，但IL-4抑制IFN-γ诱导的基因表达的机制尚不清楚。CD 40是一种I型跨膜蛋白，对免疫系统的正常功能至关重要。我们先前已经表明，IFN-γ是巨噬细胞和小胶质细胞表达CD 40的最有效诱导剂。在这份报告中，我们描述了IL-4抑制IFN-γ诱导的CD 40表达的分子机制。IL-4抑制IFN-γ诱导的巨噬细胞和小胶质细胞中的CD 40基因表达，并且这种抑制依赖于STAT-6的活化。核运行和转染研究表明，IL-4介导的抑制是在转录水平。此外，IL-4对IFN-γ诱导的CD 40表达的抑制是特异性的，因为IL-4不抑制IFN-γ诱导的IFN-应答因子-1基因表达。定点诱变研究表明，人CD 40启动子中的两个STAT结合位点，即近端和远端IFN-γ激活序列，对于IL-4抑制IFN-γ诱导的CD 40启动子活性是重要的。此外，EMSA表明IL-4激活的STAT-6结合这两个STAT结合位点。这些结果表明，IL-4对IFN-γ诱导的CD 40基因表达的抑制是通过STAT-6直接结合CD 40启动子介导的。
The antagonism between the cytokines IFN-gamma and IL-4 is well documented, but the mechanism by which IL-4 inhibits IFN-gamma-induced gene expression is not clearly understood. CD40 is a type I transmembrane protein that is critical for proper functioning of the immune system. We have previously shown that IFN-gamma is the most potent inducer of CD40 expression by macrophages and microglia. In this report, we describe the molecular mechanisms by which IL-4 inhibits IFN-gamma-induced CD40 expression. IL-4 suppresses IFN-gamma-induced CD40 gene expression in both macrophages and microglia, and such inhibition is dependent on the activation of STAT-6. Nuclear run-on and transfection studies indicate that IL-4-mediated repression is at the transcriptional level. Furthermore, IL-4 inhibition of IFN-gamma-induced CD40 expression is specific, since IL-4 does not inhibit IFN-gamma-induced IFN-responsive factor-1 gene expression. Site-directed mutagenesis studies demonstrate that two STAT binding sites, named proximal and distal IFN-gamma-activated sequences, in the human CD40 promoter are important for IL-4 inhibition of IFN-gamma-induced CD40 promoter activity. Moreover, EMSAs indicate that IL-4-activated STAT-6 binds to these two STAT binding sites. These results suggest that IL-4 inhibition of IFN-gamma-induced CD40 gene expression is mediated by direct STAT-6 binding to the CD40 promoter.