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.
Kim
K D
KD
Cell Biology Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon, South Korea.
Choe
Y K
YK
Choe
I S
IS
Lim
J S
JS
D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation; D015870:Gene Expression; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology
D000893:Anti-Inflammatory Agents; D000906:Antibodies; D019013:CD40 Antigens; D061945:Caspase Inhibitors; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D020169:Caspases