Role of the CD95/CD95 Ligand System in Glucocorticoid-Induced Monocyte Apoptosis

• Published in: The Journal of immunology (1950) 2001-01, Vol.166 (2), p.1344-1351
• Main Authors: Schmidt, Michael, Lugering, Norbert, Lugering, Andreas, Pauels, Hans-Gerd, Schulze-Osthoff, Klaus, Domschke, Wolfram, Kucharzik, Torsten
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Antibodies, Monoclonal - pharmacology; Apoptosis - drug effects; Apoptosis - immunology; Caspase 3; Caspase 8; Caspase 9; Caspases - metabolism; Caspases - physiology; CD95 antigen; CD95L protein; Cells, Cultured; Dexamethasone - metabolism; Dexamethasone - pharmacology; Enzyme Activation - immunology; Fas Ligand Protein; fas Receptor - biosynthesis; fas Receptor - immunology; fas Receptor - metabolism; fas Receptor - physiology; Humans; Hydrolysis; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Ligands; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - immunology; Membrane Glycoproteins - physiology; Monocytes - cytology; Monocytes - enzymology; Monocytes - immunology; Monocytes - ultrastructure; Poly(ADP-ribose) Polymerases - metabolism; Receptors, Glucocorticoid - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.2.1344

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.