Hoshino Katsuaki, Sugiyama Takahiro, Matsumoto Mitsuru, Tanaka Takashi, Saito Masuyoshi, Hemmi Hiroaki, Ohara Osamu, Akira Shizuo, Kaisho Tsuneyasu
Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Suehiro-cho 1-7-22, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Nature. 2006 Apr 13;440(7086):949-53. doi: 10.1038/nature04641.
The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation. TLRs 7 and 9 can recognize nucleic acids 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. 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 IkappaB 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.
Toll样受体（TLR）家族在微生物识别和树突状细胞激活中发挥着重要作用。TLR7和TLR9能够识别核酸并触发信号级联反应，激活浆细胞样树突状细胞以产生α干扰素（IFN-α）（参考文献7、8）。TLR7/9介导的树突状细胞激活对于抗病毒免疫至关重要，但也参与了系统性红斑狼疮的发病机制，在该疾病中，由于浆细胞样树突状细胞的激活，血清IFN-α水平升高。TLR7/9诱导的IFN-α产生依赖于一种分子复合物，该复合物包含TLR接头蛋白MyD88和IFN调节因子7（IRF-7）（参考文献10 - 14），但其潜在的分子机制尚不清楚。在此，我们表明IκB激酶α（IKK-α）在TLR7/9诱导的IFN-α产生中起关键作用。在IKK-α缺陷的浆细胞样树突状细胞中，TLR7/9诱导的IFN-α产生严重受损，而炎性细胞因子的诱导虽有减少但仍会发生。激酶缺陷的IKK-α抑制了MyD88与IRF-7协同激活Ifna启动子的能力。此外，IKK-α与IRF-7结合并使其磷酸化。我们的结果确定了IKK-α在TLR7/9信号传导中的作用，并突出了IKK-α作为操纵TLR诱导的IFN-α产生的潜在靶点。
