p48/STAT-1α-Containing Complexes Play a Predominant Role in Induction of IFN-γ-Inducible Protein, 10 kDa (IP-10) by IFN-γ Alone or in Synergy with TNF-α
p48/STAT-1α-Containing Complexes Play a Predominant Role in Induction of IFN-γ-Inducible Protein, 10 kDa (IP-10) by IFN-γ Alone or in Synergy with TNF-α
复制标题
含 p48/STAT-1α 的复合物在 IFN-γ 单独诱导或与 TNF-α 协同诱导 IFN-γ 诱导蛋白 10 kDa (IP-10) 中发挥主导作用
作者：
S. Majumder;L. Zhou;P. Chaturvedi;G. Babcock;S. Aras;R. Ransohoff
人IFN-γ诱导蛋白，10 kDa（hIP-10）和鼠IP-10（mIP-10）基因由IFN-γ单独诱导，并由TNF-α和IFN-γ协同诱导。人和鼠基因的上游区域含有保守的调控基序，包括IFN刺激的应答元件（ISRE），其控制mIP-10基因对IFN-γ的应答。通过ISRE介导IFN-γ应答的反式作用因子仍然不完全确定。我们研究了ISRE结合因子在hIP-10基因调控中的作用。使用p48缺陷的U2 A细胞证明了在有或没有TNF-α的情况下，IFN-γ诱导hIP-10需要p48。一个hIP-10启动子报告突变体（mISRE 3），这是相对缺乏的结合相关的因子，干扰素调节因子-1（IRF-1），但主管结合p48，诱导以及野生型hIP-10启动子，支持的解释，p48在hIP-10转录中发挥了必要和充分的作用。基因组体内足迹法显示ISRE处的IFN-γ/TNF-α诱导型结合与p48和相关因子的存在一致，但与IRF-1不一致。TNF-α/IFN-γ诱导hIP-10也需要NFκB结合位点，这些位点在体内受到保护，在体外与p65同源二聚体NFκB结合。这些结果证明了p48（与STAT-1α复合）在诱导和维持IP-10基因转录中的重要作用，强烈表明这些炎性细胞因子诱导IP-10不需要IRF-1。
Human IFN-γ-inducible protein, 10 kDa (hIP-10) and murine IP-10 (mIP-10) genes are induced by IFN-γ alone, and synergistically induced by TNF-α and IFN-γ. Upstream regions of the human and murine genes contain conserved regulatory motifs, including an IFN-stimulated response element (ISRE), which governs response of the mIP-10 gene to IFN-γ. Trans-acting factors mediating the IFN-γ response via ISRE remain incompletely defined. We examined ISRE-binding factors in the regulation of the hIP-10 gene. The requirement of p48 for hIP-10 induction by IFN-γ, with or without TNF-α, was demonstrated using p48-deficient U2A cells. An hIP-10 promoter-reporter mutant (mISRE3) that was relatively deficient for binding a related factor, IFN regulatory factor-1 (IRF-1) but competent for binding p48, was induced as well as the wild-type hIP-10 promoter, supporting the interpretation that p48 played a necessary and sufficient role in hIP-10 transcription. Genomic in vivo footprinting revealed IFN-γ/TNF-α-inducible binding at the ISRE consistent with the presence of p48 and associated factors, but not with IRF-1. Induction of hIP-10 by TNF-α/IFN-γ also required NFκB binding sites, which were protected in vivo and bound p65 homodimeric NFκB in vitro. These results documented the essential role of p48 (complexed with STAT-1α) for induction and sustained transcription of the IP-10 gene, strongly suggesting that IRF-1 is not required for IP-10 induction by these inflammatory cytokines.
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DOI：
--
发表时间：
1994
期刊：
Journal of immunology (Baltimore, Md. : 1950)
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