Suzuki Nobutaka, Suzuki Shinobu, Duncan Gordon S, Millar Douglas G, Wada Teiji, Mirtsos Christine, Takada Hidetoshi, Wakeham Andrew, Itie Annick, Li Shyun, Penninger Josef M, Wesche Holger, Ohashi Pamela S, Mak Tak W, Yeh Wen-Chen
Amgen Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada.
Nature. 2002 Apr 18;416(6882):750-6. doi: 10.1038/nature736. Epub 2002 Mar 31.
Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.
Toll样受体（TLRs）可识别病原体相关分子模式，促炎性白细胞介素-1受体（IL-1R）家族成员在其胞质结构域中具有同源性，称为Toll/IL-1R/植物R基因同源性（TIR）结构域。由TIR介导的细胞内信号传导机制相似，髓样分化因子88（MyD88，参考文献5 - 8）和肿瘤坏死因子受体相关因子6（TRAF6，参考文献9、10）发挥关键作用。已知MyD88和TRAF6之间的信号转导涉及丝氨酸 - 苏氨酸激酶IL-1受体相关激酶1（IRAK-1）以及两种同源蛋白，即IRAK-2（参考文献12）和IRAK-M。然而，IRAK分子的生理功能仍不清楚，基因靶向研究表明，IL-1R和TLR信号传导仅部分需要IRAK-1。在此我们通过基因靶向研究表明，与果蝇Pelle蛋白密切相关的IRAK分子IRAK-4，对于动物和培养细胞对IL-1以及刺激各种TLR的配体的反应是不可或缺的。缺乏IRAK-4的动物对致死剂量的脂多糖（LPS）完全具有抗性。此外，缺乏IRAK-4的动物对病毒和细菌攻击的反应严重受损。我们的结果表明，IRAK-4在先天免疫中起重要作用。
