Cutting edge:: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway in TLR signaling
Cutting edge:: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)-dependent pathway in TLR signaling
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DOI：
10.4049/jimmunol.173.5.2913
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发表时间：
2004-09-01
影响因子：
4.4
通讯作者：
Inoue, J
中科院分区：
文献类型：
--
作者：
Gohda, J;Matsumura, T;Inoue, J
TLR的信号传导途径由含有Toll/ IL-1 R（TIR）结构域的衔接分子介导。TNF受体相关因子（TRAF）6被认为激活这些含TIR结构域的蛋白质下游的NF-κ B和MAPK，以诱导炎性细胞因子的产生。然而，TRAF 6在单个TLR信号传导中的确切作用尚未得到适当的解决。我们分析了来自TRAF 6缺陷小鼠的巨噬细胞，并进行了以下观察。在不存在TR 4F 6的情况下，1）TLR 2、TLR 5、TLR 7和TLR 9的配体不能诱导NF-κ B和MAPK的活化或炎性细胞因子的产生; 2）TLR 4配体诱导的细胞因子产生显著减少，并且观察到NF-κ B和MAPK的活化，尽管具有延迟的动力学;和3）与先前报道的发现相反，TLR 3信号传导不受影响。这些结果表明TRAF 6对于MyD 88依赖性信号传导是必需的，但对于含有TIR结构域的衔接子诱导IFN-β（TRIF）依赖性信号传导不是必需的。
Signaling pathways from TLRs are mediated by the Toll/ IL-1R(TIR)domain-containing adaptor molecules. TNF receptor-associated factor (TRAF) 6 is thought to activate NF-kappaB and MAPKs downstream of these TIR domain-containing proteins to induce production of inflammatory cytokines. However, the precise role of TRAF6 in signaling from individual TLRs has not been appropriately addressed. We analyzed macrophages from TRAF6-deficient mice and made the following observations. In the absence of TR4F6, 1) ligands for TLR2, TLR5, TLR7, and TLR9 failed to induce activation of NF-kappaB and MAPKs or production of inflammatory cytokines; 2) TLR4 ligand-induced cytokine production was remarkably reduced and activation of NF-kappaB and MAPKs was observed, albeit with delayed kinetics; and 3) in contrast with previously reported findings, TLR3 signaling was not affected. These results indicate that TRAF6 is essential for MyD88-dependent signaling but is not required for TIR domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling.