Sun Honghong, Gong Shunyou, Carmody Ruaidhri J, Hilliard Anja, Li Li, Sun Jing, Kong Li, Xu Lingyun, Hilliard Brendan, Hu Shimin, Shen Hao, Yang Xiaolu, Chen Youhai H
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell. 2008 May 2;133(3):415-26. doi: 10.1016/j.cell.2008.03.026.
Immune homeostasis is essential for the normal functioning of the immune system, and its breakdown leads to fatal inflammatory diseases. We report here the identification of a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, designated TIPE2, that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues, and its deletion in mice leads to multiorgan inflammation, splenomegaly, and premature death. TIPE2-deficient animals are hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor (TLR) and T cell receptor (TCR) activation. Importantly, TIPE2 binds to caspase-8 and inhibits activating protein-1 and nuclear factor-kappaB activation while promoting Fas-induced apoptosis. Inhibiting caspase-8 significantly blocks the hyper-responsiveness of TIPE2-deficient cells. These results establish that TIPE2 is an essential negative regulator of TLR and TCR function, and its selective expression in the immune system prevents hyperresponsiveness and maintains immune homeostasis.
免疫稳态对于免疫系统的正常运作至关重要，其失衡会导致致命的炎症性疾病。我们在此报告肿瘤坏死因子-α诱导蛋白8（TNFAIP8）家族的一个成员的鉴定，该成员命名为TIPE2，它是维持免疫稳态所必需的。TIPE2在淋巴组织中优先表达，其在小鼠中的缺失会导致多器官炎症、脾肿大和过早死亡。TIPE2缺陷的动物对败血症休克高度敏感，TIPE2缺陷的细胞对Toll样受体（TLR）和T细胞受体（TCR）激活反应过度。重要的是，TIPE2与半胱天冬酶-8结合，抑制活化蛋白-1和核因子-κB的激活，同时促进Fas诱导的细胞凋亡。抑制半胱天冬酶-8可显著阻断TIPE2缺陷细胞的过度反应。这些结果表明，TIPE2是TLR和TCR功能的重要负调节因子，其在免疫系统中的选择性表达可防止反应过度并维持免疫稳态。
