Chang Seon Hee, Park Heon, Dong Chen
Department of Immunology, M D Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 2006 Nov 24;281(47):35603-7. doi: 10.1074/jbc.C600256200. Epub 2006 Oct 11.
Interleukin (IL)-17, the founding member of the IL-17 cytokine family, is the hallmark of a novel subset of CD4+ T cells that is regulated by TGFbeta, IL-6, and IL-23. IL-17 plays an important role in promoting tissue inflammation in host defense against infection and in autoimmune diseases. Although IL-17 has been reported to regulate the expression of proinflammatory cytokines, chemokines, and matrix metalloproteinases, the signaling mechanism of IL-17 receptor has not been understood. An earlier study found that IL-17 activates NF-kappaB and MAPK pathways and requires TRAF6 to induce IL-6. However, it is unknown what molecule(s) directly associates with IL-17 receptor to initiate the signaling. We demonstrate here that IL-17 receptor family shares sequence homology in their intracellular region with Toll-IL-1 receptor (TIR) domains and with Act1, a novel adaptor previously reported as an NF-kappaB activator. MyD88 and IRAK4, downstream signaling components of TIR, are not required for IL-17 signaling. On the other hand, Act1 and IL-17 receptor directly associate likely via homotypic interaction. Deficiency of Act1 in fibroblast abrogates IL-17-induced cytokine and chemokine expression, as well as the induction of C/EBPbeta, C/EBPdelta, and IkappaBzeta. Also, absence of Act1 results in a selective defect in IL-17-induced activation of NF-kappaB pathway. These results thus indicate Act1 as a membrane-proximal adaptor of IL-17 receptor with an essential role in induction of inflammatory genes. Our study not only for the first time reveals an immediate signaling mechanism downstream of an IL-17 family receptor but also has implications in therapeutic treatment of various immune diseases.
白细胞介素（IL）-17是IL-17细胞因子家族的首个成员，是由转化生长因子β（TGFβ）、IL-6和IL-23调节的新型CD4 + T细胞亚群的标志。IL-17在宿主抵御感染和自身免疫性疾病的组织炎症促进中起重要作用。尽管已有报道称IL-17可调节促炎细胞因子、趋化因子和基质金属蛋白酶的表达，但IL-17受体的信号传导机制尚不清楚。一项较早的研究发现，IL-17激活核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）途径，并需要肿瘤坏死因子受体相关因子6（TRAF6）来诱导IL-6。然而，尚不清楚何种分子直接与IL-17受体结合以启动信号传导。我们在此证明，IL-17受体家族在其细胞内区域与Toll样白细胞介素-1受体（TIR）结构域以及与Act1（一种先前报道为NF-κB激活剂的新型衔接蛋白）具有序列同源性。TIR的下游信号传导成分髓样分化因子88（MyD88）和白细胞介素-1受体相关激酶4（IRAK4）并非IL-17信号传导所必需。另一方面，Act1和IL-17受体可能通过同型相互作用直接结合。成纤维细胞中Act1的缺陷消除了IL-17诱导的细胞因子和趋化因子表达，以及C/EBPβ、C/EBPδ和IkappaBζ的诱导。此外，Act1的缺失导致IL-17诱导的NF-κB途径激活出现选择性缺陷。因此，这些结果表明Act1是IL-17受体的膜近端衔接蛋白，在炎症基因的诱导中起关键作用。我们的研究不仅首次揭示了IL-17家族受体下游的直接信号传导机制，而且对各种免疫疾病的治疗具有启示意义。
