Roles of IKK-β, IRF1, and p65 in the Activation of Chemokine Genes by Interferon-γ
Roles of IKK-β, IRF1, and p65 in the Activation of Chemokine Genes by Interferon-γ
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DOI：
10.1089/jir.2009.0034
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发表时间：
2009-12-01
影响因子：
2.3
通讯作者：
Stark, George R.
中科院分区：
文献类型：
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作者：
Shultz, David B.;Rani, M. R. Sandhya;Stark, George R.
响应干扰素（IFN）-γ或NF-κ B的趋化因子基因的活化是炎症的一个重要方面。以小鼠胚胎成纤维细胞中的趋化因子基因ip-10为例，我们表明对IFN-γ的反应是持久的，但是次要的：初始STAT 1激活驱动IRF 1合成，然后IRF 1结合到ip-10启动子中的IFN刺激的调控元件（ISRE）。大多数IKK-β依赖性IFN刺激基因（ISG）的启动子也含有ISRE。在对IFN-γ的应答中，需要NF-κ B（I κ B）激酶β（IKK-β）抑制剂来激活新合成的IRF 1和NF-κ B的p65亚基，其通过结合ip-10启动子中的κ B位点而促进ip-10表达，而经典NF-κ B很少或没有激活。与IFN-γ相反，IL-1 β通过激活经典NF-κ B和增加IRF 1的合成，快速但短暂地诱导ip-10表达。IL-1 β和IFN-γ共同协同诱导ip-10。IFN-γ不影响IL-1 β对经典NF-κ B的瞬时激活，并且即使在经典NF-κ B的激活恢复到基础水平后，IFN-γ和IL-1 β对ip-10表达的协同诱导也会发生。因此，IKK-κ通过其IRF 1和p65的活化在IFN-γ依赖性的趋化因子基因表达活化中具有新的作用。
Activation of chemokine genes in response to interferon (IFN)-gamma or NF-kappa B is an important aspect of inflammation. Using the chemokine gene ip-10 in mouse embryonic fibroblast cells as an example, we show that the response to IFN-gamma is long lasting but secondary: initial STAT1 activation drives IRF1 synthesis, and IRF1 then binds to IFN-stimulated regulatory elements (ISREs) in the ip-10 promoter. The promoters of most IKK-beta-dependent IFN-stimulated genes (ISGs) also contain ISREs. In response to IFN-gamma, inhibitor of NF-kappa B (I kappa B) kinase beta (IKK-beta) is required to activate both newly synthesized IRF1 and the p65 subunit of NF-kappa B, which contributes to ip-10 expression by binding to kappa B sites in the ip-10 promoter, with little or no activation of classical NF-kappa B. In contrast to IFN-gamma, IL-1 beta induces ip-10 expression rapidly but transiently, by activating classical NF-kappa B and increasing the synthesis of IRF1. Together, IL-1 beta and IFN-gamma induce ip-10 synergistically. IFN-gamma does not affect the transient activation of classical NF-kappa B by IL-1 beta and synergistic induction of ip-10 expression by IFN-gamma and IL-1 beta occurs even after the activation of classical NF-kappa B has returned to basal levels. Therefore, IKK-kappa has a novel role in IFN-gamma-dependent activation of chemokine gene expression through its activation of IRF1 and p65.