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

Glucocorticoids (GC) are potent anti‐inflammatory and immunosuppressive agents that act on a variety of immune cells, including T cells, monocytes/macrophages, osteoclasts, and dendritic cells (DC). However, the mechanism(s) by 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 induction of DC by a synthetic GC, dexamethasone (Dex). The stimulation with Dex resulted in DC apoptosis in a dose‐ and time‐dependent manner as it was measured by determining annexin V‐positive cells and mitochondrial potential. In contrast, monocytes that are precursor cells of DC are resistant to Dex‐mediated apoptosis. The Dex‐induced apoptosis of DC was independent of caspase activation because it was not inhibited by the broad caspase inhibitor, Z‐VAD‐fmk. It is interesting that agonistic CD40 antibody completely inhibited Dex‐induced cell death, whereas other inflammatory stimuli did not show the same effect, suggesting that CD40 signaling may selectively modulate GC‐mediated DC apoptosis. Taken together, our findings revealed an important role of GC and CD40 signaling in the regulation of immune responses in which DC play a key role in the inflammatory process of various immunomediated diseases.