Interferon response induced by Toll-like receptor signaling
Interferon response induced by Toll-like receptor signaling
复制标题
DOI：
10.1179/096805104225005896
复制
发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Takeuchi, O;Hemmi, H;Akira, S
Toll样受体（TLR）是识别不同病原体相关分子模式（PAMP）所必需的。TLR的活化诱导细胞内信号传导途径，其导致促炎细胞因子、趋化因子和干扰素（IFN）诱导基因的产生。含有TIR结构域的衔接子分子进而决定应答的信号传导特异性。最近的研究表明，丝氨酸/苏氨酸激酶IKK-1/TBK 1是调节IFN-β以及IFN-诱导基因的关键。在脂多糖（LPS），聚（I：C）和病毒感染的转染，胚胎成纤维细胞（MEFs）来自TBK 1缺陷（TBK 1-/-）小鼠显示干扰素诱导基因的生产受损，但不是促炎细胞因子。虽然IKK-i（-/-）小鼠显示这些基因的正常产生，但来自IKK-i/TBK 1-双缺陷小鼠的MEF在响应poly（I：C）刺激的IFN-β诱导以及IFN诱导基因的诱导方面完全缺陷。在IKK-i/TBK 1双缺陷细胞中，响应于LPS和poly（I：C）的IFN调节因子（IRF）3的激活被消除。有趣的是，胞内转导的聚（I：C）启动激活IFN应答的TLR 3-独立的方式。这些观察结果表明IKK-i/TBK 1信号传导对于TLR 3依赖性和TLR 3非依赖性病毒和dsRNA诱导的IFN应答都是必需的。
Toll-like receptors (TLRs) are essential for the recognition of distinct pathogen-associated molecular patterns (PAMPs). Activation of TLRs induces intracellular signaling pathways which lead to the production of pro-inflammatory cytokines, chemokines, and interferon (IFN)-inducible genes. TIR domain containing adaptor molecules in turn determine the signaling specificity of the response. Recent studies demonstrated that serine/threonine kinases IKK-i/TBK1 are critical for the regulation of IFN-beta as well as IFN-inducible genes. In response to lipopolysaccharide (LPS), transfection of poly(I: C) and viral infection, embryonic fibroblasts (MEFs) derived from TBK1-deficient (TBK1-/-) mice show impaired production of IFN-inducible genes, but not proinflammatory cytokines. Although IKK-i(-/-) mice show normal production of these genes, MEFs from IKK-i/TBK1-doubly deficient mice were completely defective in the induction of IFN-beta as well as IFN-inducible genes in response to poly(I:C) stimulation. Activation of IFN-regulatory factor (IRF) 3 in response to LPS and poly( I: C) was abolished in IKK-i/TBK1 doubly deficient cells. Interestingly, intracellular transduction of poly( I: C) initiates activation of IFN response in a TLR3-independent manner. These observations demonstrate that IKK-i/TBK1 signaling is essential for both TLR3-dependent and TLR3-independent viral and dsRNA-induced IFN responses.