Inhibition of glucocorticoid-mediated, caspase-independent dendritic cell death by CD40 activation

Glucocorticoids (GC) are potent antiinflammatory and immunosuppressive agen ts that act on a variety of immune cells, including T cells, monocytes/macr ophages, osteoclasts, and dendritic cells (DC), However, the mechanism(s) b y which GC exert anti-inflammatory effects is still largely unknown. It is already well known that GC treatment inhibits DC maturation and interleukin (IL)-12 production by DC. In this study, we investigated the apoptosis ind uction of DC by a synthetic GC, dexamethasone (Dex), The stimulation with D ex resulted in DC apoptosis in a dose- and time-dependent manner as it was measured by determining annexin V-positive cells and mitochondrial potentia l. In contrast, monocytes that are precursor cells of DC are resistant to D ex-mediated apoptosis. The Dex-induced apoptosis of DC was independent of c aspase activation because it was not inhibited by the broad caspase inhibit or, Z-VAD-fmk, It is interesting that agonistic CD40 antibody completely in hibited Dex-induced cell death, whereas other inflammatory stimuli did not show the same effect, suggesting that CD40 signaling may selectively modula te CC-mediated DC apoptosis, Taken together, our findings revealed an impor tant role of GC: and CD40 signaling in the regulation of immune responses i n which DC play a key role in the inflammatory process of various immunomed iated diseases.