IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFNγ-responsive promoters in macrophages
IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFNγ-responsive promoters in macrophages
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DOI：
10.1073/pnas.97.1.91
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发表时间：
2000-01-04
影响因子：
11.1
通讯作者：
Ozato, K
中科院分区：
文献类型：
--
作者：
Contursi, C;Wang, IM;Ozato, K
干扰素-γ，曾被称为巨噬细胞激活因子，刺激巨噬细胞中的许多基因，最终导致天然免疫的激发。干扰素的功能依赖于STAT1的激活，STAT1通过GAS元件刺激干扰素诱导基因的转录。干扰素共有序列结合蛋白(ICSBγ或干扰素调节因子8)编码干扰素调节因子家族的转录因子，是巨噬细胞中干扰素γ诱导的基因之一。我们发现，ICSBP-/-小鼠的巨噬细胞即使能够激活STAT1来响应干扰素-γ，但在诱导某些干扰素-γ反应基因方面存在缺陷。相应地，在ICSBP-/-巨噬细胞中，融合了GAS元件的荧光素酶报告分子的干扰素-γ活性严重受损，但ICSBP的转染会显著刺激这些报告分子。与激活干扰素-γ反应启动子的作用一致，ICSBP以气体特异性的方式刺激报告活性，即使在没有干扰素-γ处理的情况下，在STAT1阴性细胞中也是如此。DMA亲和结合分析表明，这种刺激的机制表明，内源性ICSBP被招募到与GAS结合的多蛋白复合体中。这些结果表明，当干扰素γ通过STAT1诱导ICSBP时，ICSBP反过来又从含GAS的启动子中产生第二波转录，从而有助于激发干扰素γ在免疫细胞中的独特活性。
IFN gamma, once called the macrophage-activating factor, stimulates many genes in macrophages, ultimately leading to the elicitation of innate immunity. IFN gamma's functions depend on the activation of STAT1, which stimulates transcription of IFN gamma-inducible genes through the GAS element. The IFN consensus sequence binding protein (icsb gamma or IFN regulatory factor 8), encoding a transcription factor of the IFN regulatory factor family, is one of such IFN gamma-inducible genes in macrophages. We found that macrophages from ICSBP-/- mice were defective in inducing some IFN gamma-responsive genes, even though they were capable of activating STAT1 in response to IFN gamma. Accordingly, IFN gamma activation of luciferase reporters fused to the GAS element was severely impaired in ICSBP-/- macrophages, but transfection of ICSBP resulted in marked stimulation of these reporters. Consistent with its role in activating IFN gamma-responsive promoters, ICSBP stimulated reporter activity in a GAS-specific manner, even in the absence of IFN gamma treatment, and in STAT1 negative cells. Indicative of a mechanism for this stimulation, DMA affinity binding assays revealed that endogenous ICSBP was recruited to a multiprotein complex that bound to GAS. These results suggest that ICSBP, when induced by IFN gamma through STAT1, in turn generates a second wave of transcription from GAS-containing promoters, thereby contributing to the elicitation of IFN gamma's unique activities in immune cells.