title: Stimulation of Fas (CD95) induces production of pro-inflammatory mediators through ERK/JNK-dependent activation of NF-κB in THP-1 cells.
abstract: Although Fas is known to be an apoptosis triggering molecule, accumulating studies indicate that Fas has non-apoptotic functions in certain cases. In an effort to identify the role of Fas in macrophage function, the human macrophage-like cell line THP-1 was analyzed after treatment with agonistic anti-Fas monoclonal antibody or co-incubation with FasL-expressing cells. Stimulation of Fas induced the expression of pro-inflammatory mediators such as matrix metalloproteinase (MMP)-9 and IL-8. The specificity of the reaction was confirmed by the transfection of Fas-specific siRNAs which resulted in a suppression of Fas expression as well as the responsiveness to the agonistic antibody. Utilization of various signaling inhibitors and ELISA-based NF-κB DNA binding assay demonstrated that the signaling initiated from Fas is mediated by mitogen activated protein kinases (MAPKs) including extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) which induce subsequent activation of NF-κB. Furthermore, mixed cell culture experiment demonstrated that Fas can be activated through interaction with membrane-bound form of FasL during cell-to-cell interaction. These data indicate that Fas plays a role as an activation inducing molecule through interaction with its counterpart and Fas-mediate events are mediated by ERK/JNK MAPKs which subsequently activate NF-κB for the transcriptional activation of pro-inflammatory mediators.
authors.affiliation: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of 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 / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D015153:Blotting, Western; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D048049:Extracellular Signal-Regulated MAP Kinases; D053222:Fas Ligand Protein; D018836:Inflammation Mediators; D016209:Interleukin-8; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D019014:fas Receptor; C411023:anti-Fas monoclonal antibody; C535150:MAPK1 protein, human