Role of the CD95/CD95 ligand system in glucocorticoid-induced monocyte apoptosis

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 apoptos is in human peripheral blood monocytes. In the present study, we examined t he signaling pathway in GC-induced apoptosis. Monocyte apoptosis was demons trated by annexin V staining, DNA laddering, and electron microscopy. Apopt osis required the activation of caspases, as different caspase inhibitors p revented GC-induced cell death. In addition, the proteolytic activation of caspase-8 and caspase-3 was observed. In additional experiments, we determi ned the role of the death receptor CD95 in GC-induced apoptosis, CD95 and C D95 ligand (CD95L) were up-regulated in a dose- and time-dependent manner o n the cell membrane and also released after treatment with GC. Costimulatio n with the GC receptor antagonist mifepristone diminished monocyte apoptosi s as well as CD95/CD95L expression and subsequent caspase-8 and caspase-3 a ctivation. In contrast, the caspase inhibitor N-acetyl-Asp-Glu-Val-Asp-alde hyde suppressed caspase-3 activation and apoptosis, but did not down-regula te caspase-8 activation and expression of CD95 and CD95L. Importantly, GC-i nduced monocyte apoptosis was strongly abolished by a neutralizing CD95L mA b. Therefore, our data suggest that GC-induced monocyte apoptosis is at lea st partially mediated by an autocrine or paracrine pathway involving the CD 95/CD95L system.