Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction.
Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction.
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DOI：
10.1084/jem.191.7.1233
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发表时间：
2000-04-03
期刊：
影响因子：
--
通讯作者：
Cao Z
中科院分区：
文献类型：
--
作者：
Schwandner R;Yamaguchi K;Cao Z
白介素17通过其广泛分布的细胞表面受体传递信号，促进致炎分子编码基因的转录。尽管已有文献证明IL-17可激活转录因子核因子-κB和c-Jun氨基末端激酶，但其上游信号转导机制尚不清楚。在此，我们报道了肿瘤坏死因子受体相关因子(TRAF6)在IL-17诱导的NF-κB和JNK活化中的作用。在TRAF6基因敲除小鼠的胚胎成纤维细胞中，IL-17不能激活IκB激酶和JNK。因此，IL-17诱导的TRAF6缺陷细胞中IL-6和细胞间黏附分子1的表达被取消。缺乏TRAF6似乎是导致观察到的对IL-17反应失败的唯一原因，因为瞬时将TRAF6表达载体导入TRAF6缺陷细胞，在荧光素酶报告实验中恢复了IL-17诱导的NF-κB的激活。此外，TRAF6缺陷EFS上的IL-17受体(IL-17R)水平与野生型对照细胞相当。在TRAF2缺乏的EFS中未观察到IL-17反应缺陷。此外，当TRAF6和IL-17R在293细胞中共表达时，TRAF6与IL-17R共沉淀。综上所述，这些结果表明，TRAF6，而不是TRAF2，是导致促炎反应的IL-17信号通路中的关键成分。
Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-κB and c-Jun NH2-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor–associated factor (TRAF)6 in IL-17–induced NF-κB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IκB kinases (IKKs) and JNK. Consequently, IL-17–induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17–induced NF-κB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses.
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