https://scholars.lib.ntu.edu.tw/handle/123456789/160947
標題: | Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling | 作者: | Wu, Yu-Jung Wu, Yung-Hsuan Mo, Shu-Ting Hsiao, Huey-Wen He, You-Wen Lai, Ming-Zong |
公開日期: | 2015 | 起(迄)頁: | 2612-2623 | 來源出版物: | The Journal of Immunology | 摘要: | Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor-induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b(+) conventional DCs (cDCs), CD8(+) cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow-derived DCs (BMDCs) displayed enhanced production of TNF-alpha, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP+/- macrophages. Additionally, the increased activation in c-FLIP-deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/278973 | DOI: | 10.4049/jimmunol.1402944 | SDG/關鍵字: | caspase 8; CD11b antigen; dectin 1; FLICE inhibitory protein; granulocyte colony stimulating factor; interleukin 2; mitogen activated protein kinase p38; toll like receptor 2; toll like receptor 4; tumor necrosis factor alpha; antiinflammatory agent; B7 antigen; Casp8 protein, mouse; caspase 8; CD86 antigen; Cd86 protein, mouse; Cflar protein, mouse; dectin 1; FLICE inhibitory protein; granulocyte colony stimulating factor; HLA antigen class 2; interleukin 2; lectin; mitogen activated protein kinase p38; small interfering RNA; Tlr2 protein, mouse; Tlr4 protein, mouse; toll like receptor 2; toll like receptor 4; tumor necrosis factor alpha; animal cell; animal experiment; animal tissue; Article; bone marrow cell; cell activation; cell population; cell viability; cellular immunity; controlled study; cytokine production; down regulation; enzyme activation; enzyme activity; innate immunity; macrophage; mouse; nonhuman; plasmacytoid dendritic cell; priority journal; protein expression; signal transduction; animal; antagonists and inhibitors; antigen presentation; apoptosis; biosynthesis; bone marrow cell; cytology; dendritic cell; genetics; immunology; inflammation; knockout mouse; leukocyte count; metabolism; neutrophil; RNA interference; splenomegaly; T lymphocyte; Animals; Anti-Inflammatory Agents; Antigen Presentation; Antigens, CD80; Antigens, CD86; Apoptosis; Bone Marrow Cells; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Dendritic Cells; Enzyme Activation; Granulocyte Colony-Stimulating Factor; Histocompatibility Antigens Class II; Inflammation; Interleukin-2; Lectins, C-Type; Leukocyte Count; Mice; Mice, Knockout; Myeloid Cells; Neutrophils; p38 Mitogen-Activated Protein Kinases; RNA Interference; RNA, Small Interfering; Signal Transduction; Splenomegaly; T-Lymphocytes; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha |
顯示於: | 免疫學研究所 |
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