Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors
Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors
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DOI：
10.1038/nature03308
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发表时间：
2005-03-10
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, T
中科院分区：
文献类型：
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作者：
Takaoka, A;Yanai, H;Taniguchi, T
Toll样受体（TLR）的激活是先天性和适应性免疫的核心（1-3）。所有TLR都使用衔接子MyD 88进行信号传导（4），但MyD 88介导的基因诱导程序的机制尚未完全了解。在这里，我们证明，转录因子IRF-5通常参与下游的TLR-MyD 88信号通路的基因诱导的促炎细胞因子，如白细胞介素-6（IL-6），IL-12和肿瘤坏死因子-α。在来自Irf 5基因缺陷小鼠（Irf 5（-/-）小鼠）的造血细胞中，由各种TLR配体对这些细胞因子的诱导严重受损，而干扰素-α诱导是正常的。我们还提供了IRF-5与MyD 88和TRAF 6相互作用并被MyD 88和TRAF 6激活的证据，并且TLR激活导致IRF-5的核转位以激活细胞因子基因转录。一致地，Irf 5（-/-）小鼠显示对由未甲基化DNA或脂多糖诱导的致死性休克的抗性，这与促炎细胞因子的血清水平的显著降低相关。因此，我们的研究将IRF-5确定为TLR-MyD 88信号通路的新的主要下游调节因子，以及控制有害免疫反应的治疗干预的潜在靶点。
The activation of Toll-like receptors (TLRs) is central to innate and adaptive immunity(1-3). All TLRs use the adaptor MyD88 for signalling(4), but the mechanisms underlying the MyD88-mediated gene induction programme are as yet not fully understood. Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5(-/-) mice), the induction of these cytokines by various TLR ligands is severely impaired, whereas interferon-alpha induction is normal. We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6, and that TLR activation results in the nuclear translocation of IRF-5 to activate cytokine gene transcription. Consistently, Irf5(-/-) mice show resistance to lethal shock induced by either unmethylated DNA or lipopolysaccharide, which correlates with a marked decrease in the serum levels of proinflammatory cytokines. Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.