IL-1 receptor-associated kinase modulates host responsiveness to endotoxin
IL-1 receptor-associated kinase modulates host responsiveness to endotoxin
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DOI：
10.4049/jimmunol.164.8.4301
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发表时间：
2000-04-15
影响因子：
4.4
通讯作者：
Thomas, JA
中科院分区：
文献类型：
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作者：
Swantek, JL;Tsen, MF;Thomas, JA
内毒素引发革兰氏阴性菌感染性休克的许多炎症、血流动力学和血液学紊乱。最近在小鼠中的遗传学研究已经确定Toll样受体4为跨膜内毒素信号转导器。IL-1细胞内信号传导通路与Toll样受体信号转导有关。LPS诱导的IL-1受体相关激酶（IRAK）的活化，以及IRAK对细胞内信号传导和细胞内毒素应答的影响尚未在相关的先天免疫细胞中进行研究。我们证明LPS激活小鼠巨噬细胞中的IRAK，相反，IRAK缺陷的巨噬细胞对LPS具有抗性。IRAK的缺失破坏了几个内毒素触发的信号级联。此外，缺乏IRAK的巨噬细胞表现出LPS刺激的TNF-α产生受损，IRAK缺陷小鼠耐受LPS的致死作用。这些发现，加上IRAK在IL-1和IL-18信号转导中的关键作用，证明了这种激酶和IL-1/Toll信号传导盒在感测和响应革兰氏阴性感染中的重要性。
Endotoxin triggers many of the inflammatory, hemodynamic, and hematological derangements of Gram-negative septic shock. Recent genetic studies in mice have identified the Toll-like receptor 4 as the transmembrane endotoxin signal transducer. The IL-1 intracellular signaling pathway has been implicated in Toll-like receptor signal transduction. LPS-induced activation of the IL-1 receptor-associated kinase (IRAK), and the influence of IRAK on intracellular signaling and cellular responses to endotoxin has not been explored in relevant innate immune cells. We demonstrate that LPS activates IRAK in murine macrophages, IRAK-deficient macrophages, in contrast, are resistant to LPS. Deletion of IRAK disrupts several endotoxin-triggered signaling cascades. Furthermore, macrophages lacking IRAK exhibit impaired LPS-stimulated TNF-alpha production, and IRAK-deficient mice withstand the lethal effects of LPS, These findings, coupled with the critical role for IRAK in IL-1 and IL-18 signal transduction, demonstrate the importance of this kinase and the IL-1/Toll signaling cassette in sensing and responding to Gram-negative infection.