Qian Youcun, Liu Caini, Hartupee Justin, Altuntas Cengiz Zubeyir, Gulen Muhammet Fatih, Jane-Wit Daniel, Xiao Jianhua, Lu Yi, Giltiay Natalia, Liu Jinbo, Kordula Tomasz, Zhang Qi-Wei, Vallance Bruce, Swaidani Shadi, Aronica Mark, Tuohy Vincent K, Hamilton Thomas, Li Xiaoxia
Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nat Immunol. 2007 Mar;8(3):247-56. doi: 10.1038/ni1439. Epub 2007 Feb 4.
T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-kappaB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate-induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.
产生白细胞介素17（IL-17）的辅助性T细胞与炎症及某些细菌的控制有关。我们在此报告衔接蛋白Act1在IL-17受体（IL-17R）信号传导及IL-17依赖性免疫反应中的重要作用。用IL-17刺激后，Act1募集至IL-17R需要IL-17R保守的胞质“SEFIR”结构域，随后募集激酶TAK1和E3泛素连接酶TRAF6，它们介导转录因子NF-κB的“下游”激活。在Act1缺陷的原代星形胶质细胞和肠道上皮细胞中，IL-17诱导的炎症相关基因表达被消除。这种减少与自身免疫性脑脊髓炎和葡聚糖硫酸钠诱导的结肠炎体内炎症性疾病的大幅减轻有关。我们的数据表明，Act1在自身免疫和炎症性疾病的IL-17依赖性信号传导中至关重要。
