title: Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling.
abstract: 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-α, 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.
authors.affiliation: Institute of Immunology, National Taiwan University, Taipei 10051, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Yung-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Mo
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Huey-Wen
authors.initials: HW
authors.lastname: Hsiao
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.affiliation: Institute of Immunology, National Taiwan University, Taipei 10051, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and mblai@gate.sinica.edu.tw.
authors.forename: Ming-Zong
authors.identifier: http://orcid.org/0000-0002-3237-4803
authors.initials: MZ
authors.lastname: Lai
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000276:immunology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000276:immunology*; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000276:immunology; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D013163:Splenomegaly / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D000893:Anti-Inflammatory Agents; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D016179:Granulocyte Colony-Stimulating Factor; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D037181:Lectins, C-Type; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099181:Dectin-1; C497965:Cd86 protein, mouse; C506387:Cflar protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C505526:Casp8 protein, mouse