臺大醫學院-免疫學研究所;Wu, Y-HY-HWuKuo, W-CW-CKuoWu, Y-JY-JWuYang, K-TK-TYangChen, S-TS-TChenJiang, S-TS-TJiangGordy, C.C.GordyHe, Y-WY-WHeLai, M-ZM-ZLai2017-05-252018-07-092017-05-252018-07-092014http://ntur.lib.ntu.edu.tw//handle/246246/278900Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of caspase-8 and is required for macrophage survival. Recent studies have revealed a selective role of caspase-8 in noncanonical IL-1 beta production that is independent of caspase-1 or inflammasome. Here we demonstrated that c-FLIPL is an unexpected contributor to canonical inflammasome activation for the generation of caspase-1 and active IL-1 beta. Hemizygotic deletion of c-FLIP impaired ATP-and monosodium uric acid (MSU)-induced IL-1 beta production in macrophages primed through Toll-like receptors (TLRs). Decreased IL-1 beta expression was attributed to a reduced activation of caspase-1 in c-FLIP hemizygotic cells. In contrast, the production of TNF-alpha was not affected by downregulation in c-FLIP. c-FLIPL interacted with NLRP3 or procaspase-1. c-FLIP is required for the full NLRP3 inflammasome assembly and NLRP3 mitochondrial localization, and c-FLIP is associated with NLRP3 inflammasome. c-FLIP downregulation also reduced AIM2 inflammasome activation. In contrast, c-FLIP inhibited SMAC mimetic-, FasL-, or Dectin-1-induced IL-1 beta generation that is caspase-8-mediated. Our results demonstrate a prominent role of c-FLIPL in the optimal activation of the NLRP3 and AIM2 inflammasomes, and suggest that c-FLIP could be a valid target for treatment of inflammatory diseases caused by over-activation of inflammasomes.c-FLIPinflammasomeIL-1 betacaspase-1caspase-8macrophages[SDGs]SDG3AIM2 protein, human; Aim2 protein, mouse; carrier protein; CIAS1 protein, mouse; DNA binding protein; FLICE inhibitory protein; inflammasome; interleukin 1beta; NLRP3 protein, human; peptide; transfecting peptide I; animal; down regulation; genetics; HEK293 cell line; human; macrophage; metabolism; mouse; signal transduction; Animals; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; DNA-Binding Proteins; Down-Regulation; HEK293 Cells; Humans; Inflammasomes; Interleukin-1beta; Macrophages; Mice; Peptides; Signal Transduction10.1038/cdd.2013.165