title: Stimulation of FasL induces production of proinflammatory mediators through activation of mitogen-activated protein kinases and nuclear factor-κB in THP-1 cells.
abstract: FasL is a member of the tumor necrosis factor (TNF) superfamily involved in the various immune reactions such as activation-induced cell death, cytotoxic effector function, and establishment of immune privileged sites through its interaction with Fas. On the other hand, FasL is known to transmit a reverse signal that serves as a T cell co-stimulatory signal. However, the role of FasL-mediated reverse signaling in macrophage function has not been investigated. In order to investigate the presence of FasL-mediated signaling in macrophages, the human macrophage-like cell line THP-1 was analyzed after treatment with FasL ligating agents such as recombinant Fas:Fc fusion protein or anti-FasL monoclonal antibody. Stimulation of FasL induced the expression of proinflammatory mediators such as matrix metalloproteinase-9, TNF-α, and IL-8. The specificity of the reaction was confirmed by the transfection of the FasL-specific siRNAs, which suppressed FasL expression as well as the production of proinflammatory mediators. Utilization of various inhibitors of signaling adaptors and ELISA-base nuclear factor (NF)-κB binding assay demonstrated that the signaling initiated from FasL is mediated by mitogen-activated protein kinases including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase which induce subsequent activation of NF-κB. These data indicate that membrane expression of FasL and its interaction with its counterpart may contribute to the inflammatory activation of macrophages during immune reactions or pathogenesis of chronic inflammatory diseases.
authors.affiliation: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, 702-701, South Korea.
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Lee
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Kim
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011961:Receptors, Fc / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019014:fas Receptor / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; C444139:CD300C protein, human; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9