IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9
IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9
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DOI：
10.1038/nature04641
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发表时间：
2006-04-13
期刊：
影响因子：
64.8
通讯作者：
Kaisho, T
中科院分区：
文献类型：
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作者：
Hoshino, K;Sugiyama, T;Kaisho, T
Toll样受体（TLR）家族在微生物识别和树突细胞活化中具有重要作用（1，2）。TLR 7和9可以识别核酸（3-6）并触发激活浆细胞样树突细胞产生干扰素-α（IFN-α）的信号级联（参考文献7，8）。TLR 7/9介导的树突状细胞活化对于抗病毒免疫至关重要，但也有助于系统性红斑狼疮的发病机制，系统性红斑狼疮是一种由于浆细胞样树突状细胞活化而导致血清IFN-α水平升高的疾病（8，9）。TLR 7/9诱导的IFN-α诱导依赖于含有TLR接头、MyD 88和IFN调节因子7（IRF-7）的分子复合物（参考文献10-14），但其潜在的分子机制尚不清楚。在这里，我们表明，I κ B激酶-α（IKK-α）是关键参与TLR 7/9诱导的IFN-α的生产。TLR 7/9诱导的IFN-α的产生在IKK-α缺陷的浆细胞样树突状细胞中严重受损，而炎性细胞因子的诱导减少，但仍然发生。激酶缺陷型IKK-alpha抑制MyD 88与IRF-7协同激活Ifna启动子的能力。此外，IKK-α与IRF-7相关并使其磷酸化。我们的研究结果确定了IKK-alpha在TLR 7/9信号传导中的作用，并强调IKK-alpha是操纵TLR诱导的IFN-α产生的潜在靶点。
The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation(1,2). TLRs 7 and 9 can recognize nucleic acids(3-6) and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (IFN-alpha) (refs 7, 8). TLR7/9-mediated dendritic cell activation is critical for antiviral immunity but also contributes to the pathogenesis of systemic lupus erythematosus, a disease in which serum IFN-alpha levels are elevated owing to plasmacytoid dendritic cell activation(8,9). TLR7/9-induced IFN-alpha induction depends on a molecular complex that contains a TLR adaptor, MyD88, and IFN regulatory factor 7 (IRF-7) (refs 10-14), but the underlying molecular mechanisms are as yet unknown. Here we show that I kappa B kinase-alpha (IKK-alpha) is critically involved in TLR7/9-induced IFN-alpha production. TLR7/9-induced IFN-alpha production was severely impaired in IKK-alpha-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-alpha inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-alpha associated with and phosphorylated IRF-7. Our results identify a role for IKK-alpha in TLR7/9 signalling, and highlight IKK-alpha as a potential target for manipulating TLR-induced IFN-alpha production.