Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-β production in myeloid dendritic cells
Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-β production in myeloid dendritic cells
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DOI：
10.1002/eji.200636767
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发表时间：
2007-02-01
影响因子：
5.4
通讯作者：
Wagner, Hermann
中科院分区：
文献类型：
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作者：
Schmitz, Frank;Heit, Antje;Wagner, Hermann
干扰素调节因子（IRF）-3和/或IRF-7的活化驱动抗病毒基因的表达和α/β IFN的产生，这是由Toll样受体（TLR）触发的抗病毒应答的标志。在这里，我们描述了一种新的抗病毒信号通路在髓样（m）树突状细胞（DC）和巨噬细胞，不需要IRF-3和/或IRF-7，但由IRF-1驱动。IRF-1与髓样分化因子88（MyD 88）或IL-1受体相关激酶（IRAK）-1一起触发IFN-β启动子激活。IRF-1与MyD 88发生物理相互作用，通过TLR-9激活mDC诱导IRF-1依赖性IFN-β产生，而IFN-β刺激基因的快速转录激活则可诱导IRF-1依赖性IFN-β产生。然而，NF-κ B依赖的促炎细胞因子的产生不受IRF-1的影响。TLR-9信号通过这一途径赋予细胞抗病毒抗性，而IRF-1缺陷小鼠显示出对病毒感染的易感性增强。这些结果表明，TLR-9活化mDC和巨噬细胞有助于通过IRF-1的抗病毒免疫。
Activation of interferon regulatory factor (IRF)-3 and/or IRF-7 drives the expression of antiviral genes and the production of alpha/beta IFN, a hallmark of antiviral responses triggered by Toll-like receptors (TLR). Here we describe a novel antiviral signaling pathway operating in myeloid (m) dendritic cells (DC) and macrophages that does not require IRF-3 and/or IRF-7 but is driven by IRF-1. IRF-1 together with myeloid differentiation factor 88 (MyD88) or IL-1 receptor-associated kinase (IRAK)-1 triggered IFN-beta promoter activation. IRF-1 physically interacted with MyD88 and activation of mDC via TLR-9 induced IRF-1-dependent IFN-beta production paralleled by rapid transcriptional activation of IFN-stimulated genes. The NF-kappa B-dependent production of pro-inflammatory cytokines, however, was not influenced by IRF-1. TLR-9 signaling through this pathway conferred cellular antiviral resistance while IRF-1-deficient mice displayed enhanced susceptibility to viral infection. These results demonstrate that TLR-9 activation of mDC and macrophages contributes to antiviral immunity via IRF-1.