Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4
Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4
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DOI：
10.1038/nature736
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发表时间：
2002-04-18
期刊：
影响因子：
64.8
通讯作者：
Yeh, WC
中科院分区：
文献类型：
--
作者：
Suzuki, N;Suzuki, S;Yeh, WC
Toll 样受体 (TLR) 识别病原体相关分子模式，属于促炎性白细胞介素 1 受体 (IL-1R) 家族成员，其细胞质结构域具有同源性，称为 Toll/IL-1R/植物 R 基因同源性 (TIR) 结构域 (1-3)。 TIR 介导的细胞内信号传导机制相似(4)，其中 MyD88（参考文献 5-8）和 TRAF6（参考文献 9、10）发挥着关键作用。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)(11) 和两种同源蛋白 IRAK-2（参考文献 12）和 IRAK-M-13。然而，IRAK 分子的生理功能仍不清楚，基因靶向研究表明，IRAK-1 仅是 IL-1R 和 TLR 信号传导所部分必需的 (14,15)。在这里，我们通过基因靶向表明，IRAK-4（一种与果蝇 Pelle 蛋白 16 密切相关的 IRAK 分子）对于动物和培养细胞对 IL-1 和刺激各种 TLR 的配体的反应是不可或缺的。 IRAK-4 缺陷动物对致死剂量的脂多糖 (LPS) 具有完全抵抗力。此外，缺乏IRAK-4的动物对病毒和细菌挑战的反应严重受损。我们的结果表明 IRAK-4 在先天免疫中具有重要作用。
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(1-3). Intracellular signalling mechanisms mediated by TIRs are similar(4), 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)(11) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M-13. 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(14,15). Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein 16, 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.