Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.
Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling.
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IRAK-4蛋白及其激酶活性在Toll样受体介导的免疫反应中而不是TCR信号传导中的基本作用。
DOI：
10.1084/jem.20061523
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发表时间：
2007-05-14
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白细胞介素-1受体相关激酶4（IRAK-4）是Toll样受体（TLR）和T细胞受体（TCR）介导的信号转导通路中的重要组成部分，其介导的信号转导通路可激活核因子κB（NF-κB）。然而，IRAK家族成员激酶活性的重要性尚不清楚。在这项研究中，我们研究了IRAK-4活性在体内的功能作用，通过产生小鼠携带敲入突变（KK 213 AA），废除其激酶活性。IRAK-4 KN/KN小鼠对TLR诱导的休克反应具有高度抵抗性。在IRAK-4 KN/KN以及IRAK-4 −/−巨噬细胞中，响应TLR配体的细胞因子产生严重受损。IRAK-4活性对于导致丝裂原活化蛋白激酶的信号通路的活化是必不可少的。TLR诱导的IRAK-4/IRAK-1依赖性和非依赖性途径参与了对TLR配体如肿瘤坏死因子α和IκB β的反应的NF-κ B调节基因的早期诱导。与先前的论文（Suzuki，N.，S.铃木，D.G. Millar，M. Unno，H. Hara，T.卡尔扎夏湾Yamasaki，T. Yokosuka，N.J. Chen，A.R. Elford等人，2006年。科学311：1927-1932），TCR信号传导在IRAK-4-/-和IRAK-4KN/KN小鼠中未受损。因此，IRAK-4的激酶活性对于调节TLR介导的先天免疫应答是必需的。
Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4 KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4 KN/KN as well as IRAK-4 −/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4 −/− and IRAK-4 KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.