Negative regulation of Toll-like-receptor signaling by IRF-4
Negative regulation of Toll-like-receptor signaling by IRF-4
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DOI：
10.1073/pnas.0508327102
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发表时间：
2005-11-01
影响因子：
11.1
通讯作者：
Honda, K
中科院分区：
文献类型：
--
作者：
Negishi, H;Ohba, Y;Honda, K
Toll样受体(TLRs)对微生物成分的识别是天然免疫系统和获得性免疫系统激活的中心事件。TLR激活触发下游靶基因的诱导，其中与TLR相互作用的接头分子MyD88招募各种信号分子和转录因子。干扰素调节因子(IRF)转录因子家族的两个成员，IRF-5和IRF-7，分别与MyD88相互作用，并分别诱导促炎细胞因子和I型IFN。在这里，我们证明了IRF-4也与MyD88相互作用，并作为TLR信号的负调节因子。IRF-4mRNA由TLR激活诱导，IRF-4与IRF-5竞争MyD88相互作用，而不与IRF-7竞争MyD88。在IRF4基因缺陷小鼠的腹腔巨噬细胞中，依赖TLR的促炎细胞因子的诱导显著增强，而在巨噬细胞系中IRF-4的异位表达抑制了这种诱导。观察到IRF4缺陷小鼠对DNA诱导的休克表现出超敏反应，血清促炎细胞因子水平升高，这突显了IRF-4在体内TLR信号转导中的关键作用。这项研究可能为深入了解IRF对MyD88信号的复杂调控机制提供依据。
The recognition of microbial components by Toll-like receptors (TLRs) is an event central to the activation of innate and adaptive immune systems. TLR activation triggers the induction of downstream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs.