title: Pathogen-associated molecular patterns sensitize macrophages to Fas ligand-induced apoptosis and IL-1 beta release.
abstract: Antigenic stimulation activates T cells and simultaneously destines them to die by Fas-mediated apoptosis. In this study, we demonstrated that various pathogen-associated molecular patterns up-regulated Fas expression in macrophages and sensitized them specifically to Fas ligand (FasL), but not to other apoptosis-inducing agents such as TNF-alpha, etoposide (VP-16), and staurosporine. Toll-like receptor, NF-kappaB, and p38 mitogen-activated protein kinase mediated these responses. LPS stimulation induced the expression of Fas, caspase 8, cellular FLIP Bfl-1/A1, and Bcl-x, but not FasL, TNFR p55, Bak, Bax, and Bad at the transcriptional level. Thus, LPS selectively induced the expression of apoptotic molecules of the Fas death pathway (except for cellular FLIP) and antiapoptotic molecules of the mitochondrial death pathway. However, the kinetics of macrophage disappearance following Escherichia coli-induced peritonitis was similar between wild-type and Fas-deficient mice, suggesting that Fas is not essential for the turnover of activated macrophages in T cell-independent inflammation. In contrast, LPS-activated macrophages produced a large amount of IL-1beta upon FasL stimulation. Thus, unlike the activation-induced cell death of T cells, the sensitization of macrophages to FasL by pathogen-associated molecular patterns seems to be a proinflammatory rather than an anti-inflammatory event.
authors.affiliation: Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukui
authors.forename: Ryu
authors.initials: R
authors.lastname: Imamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Umemura
authors.forename: Takaya
authors.initials: T
authors.lastname: Kawabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Suda
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002452:Cell Count; D002460:Cell Line; D053222:Fas Ligand Protein; D005260:Female; D007375:Interleukin-1 / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D051193:Toll-Like Receptors; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000276:Adjuvants, Immunologic; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007375:Interleukin-1; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D019014:fas Receptor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases