title: Dexamethasone-induced suppression of apoptosis in human neutrophils requires continuous stimulation of new protein synthesis.
abstract: We examined the mechanisms of corticosteroid inhibition of cell death by apoptosis in human neutrophils. Suppression of apoptosis by dexamethasone was abolished by co-treatment with the protein synthesis inhibitor cycloheximide. At doses of 1 microg/mL cycloheximide did not reduce basal survival of neutrophils but effectively inhibited dexamethasone-induced increases in 24-h survival (24.4 +/- 8.7 vs. 49.6 +/- 10%, P < 0.01). Similar results were obtained with actinomycin D, an inhibitor of mRNA synthesis. The factor(s) responsible for mediating increased survival following dexamethasone treatment is not active extracellularly because dexamethasone-treated neutrophil-conditioned medium (CM) had no effect on the survival of naive neutrophils when the direct effects of dexamethasone were neutralized with the steroid antagonist RU-486. In contrast, LPS-treated neutrophil CM significantly increased neutrophil survival even after addition of polymyxin b. The survival effect of dexamethasone required the continuous presence of the agonist because addition of RU-486 caused prompt development of apoptosis in dexamethasone-treated cells. When naive and dexamethasone-treated cells were examined by mRNA differential display, a limited number of cDNA bands were consistently and reproducibly detected that were increased in intensity, indicating up-regulation by dexamethasone. Thus, corticosteroid regulation of neutrophil apoptosis is a specific effect that depends on continuous stimulation of synthesis of a (protein) survival factor.
authors.affiliation: Father Sean O'Sullivan Research Centre, St. Joseph's Hospital, Hamilton, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Cox
authors.forename: R C
authors.initials: RC
authors.lastname: Austin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001798:Blood Proteins / Q000096:biosynthesis*; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D006133:Growth Substances / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000302:isolation & purification; D013997:Time Factors
chemical_list: D001798:Blood Proteins; D006133:Growth Substances; D007166:Immunosuppressive Agents; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003907:Dexamethasone