title: Role of the CD95/CD95 ligand system in glucocorticoid-induced monocyte apoptosis.
abstract: Glucocorticoids (GC) act as potent anti-inflammatory and immunosuppressive agents on a variety of immune cells. However, the exact mechanisms of their action are still unknown. Recently, we demonstrated that GC induce apoptosis in human peripheral blood monocytes. In the present study, we examined the signaling pathway in GC-induced apoptosis. Monocyte apoptosis was demonstrated by annexin V staining, DNA laddering, and electron microscopy. Apoptosis required the activation of caspases, as different caspase inhibitors prevented GC-induced cell death. In addition, the proteolytic activation of caspase-8 and caspase-3 was observed. In additional experiments, we determined the role of the death receptor CD95 in GC-induced apoptosis. CD95 and CD95 ligand (CD95L) were up-regulated in a dose- and time-dependent manner on the cell membrane and also released after treatment with GC. Costimulation with the GC receptor antagonist mifepristone diminished monocyte apoptosis as well as CD95/CD95L expression and subsequent caspase-8 and caspase-3 activation. In contrast, the caspase inhibitor N:-acetyl-Asp-Glu-Val-Asp-aldehyde suppressed caspase-3 activation and apoptosis, but did not down-regulate caspase-8 activation and expression of CD95 and CD95L. Importantly, GC-induced monocyte apoptosis was strongly abolished by a neutralizing CD95L mAb. Therefore, our data suggest that GC-induced monocyte apoptosis is at least partially mediated by an autocrine or paracrine pathway involving the CD95/CD95L system.
authors.affiliation: Departments of Medicine B and Immunology and Cell Biology, Institute for Immunology, University of Münster, Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.forename: N
authors.initials: N
authors.lastname: Lügering
authors.forename: A
authors.initials: A
authors.lastname: Lügering
authors.forename: H G
authors.initials: HG
authors.lastname: Pauels
authors.forename: K
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: W
authors.initials: W
authors.lastname: Domschke
authors.forename: T
authors.initials: T
authors.lastname: Kucharzik
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D006868:Hydrolysis; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D009000:Monocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D011965:Receptors, Glucocorticoid; D019014:fas Receptor; D003907:Dexamethasone; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases