Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway
Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway
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DOI：
10.1126/science.1087262
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发表时间：
2003-08-01
期刊：
影响因子：
56.9
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Yamamoto, M;Sato, S;Akira, S
Toll样受体（TLR）的刺激触发常见的MyD 88依赖性信号传导途径以及MyD 88非依赖性途径的激活，所述MyD 88非依赖性途径是导致干扰素（IFN）-β产生的TLR 3和TLR 4信号传导途径所特有的。在这里，我们破坏了编码Toll/IL-1受体（TIR）结构域的衔接子TRIF的基因。TRIF缺陷小鼠在TLR 3-和TLR 4-介导的IFN-β表达和IRF-3活化方面都有缺陷。此外，在TRIF缺陷的巨噬细胞中，响应于TLR 4配体而不是其它TLR配体的炎性细胞因子产生严重受损。MyD 88和TRIF两者缺陷的小鼠显示响应于TLR 4刺激的核因子κ B活化的完全丧失。这些发现表明，TRIF是必需的TLR 3和TLR 4介导的信号通路，促进哺乳动物抗病毒宿主防御。
Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-beta production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain- containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-beta and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.