Dexamethasone and methylprednisolone affect rat peritoneal phagocyte chemiluminescence after administration in vivo.
Production of reactive oxygen compounds by peritoneal monocytes/macrophages was studied in rats exposed to dexamethasone or methylprednisolone in the drinking water. Luminol-amplified chemiluminescence was measured in preparations of peritoneal leukocytes activated ex vivo by serum opsonized zymosan, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) or phorbol 12-myristate 13-acetate (PMA). After dexamethasone administration for 1 day (approximately 0.13 mg/kg per 24 h) a significant reduction in chemiluminescence was found in cells stimulated with serum opsonized zymosan, while responses to fMLP and PMA stimulation were significantly reduced after 2 days. The maximal inhibition obtained after 5-8 days of dexamethasone administration (plasma levels < 5 nM) was 92.0 +/- 1.2%, 87.6 +/- 0.2% and 84.5 +/- 3.1% in cells stimulated with serum opsonized zymosan, fMLP and PMA, respectively. Administration of dexamethasone or methylprednisolone for 48 h gave a dose-dependent reduction of chemiluminescence. ED50 values of dexamethasone were estimated at 0.06-0.15 mg/kg for the different stimulators (plasma concentrations 5-10 nM). Estimated ED50 values for methylprednisolone were 35-36 mg/kg. Since the percentage of mononuclear phagocytes in the peritoneal cell population did not change significantly with dose or time of dexamethasone exposure, this study indicates that glucocorticoids have a depressive effect on the monocyte/macrophage 'respiratory burst' in vivo. The results are consistent with the hypothesis that these effects are mediated by glucocorticoid receptors. Although the pathway activated by serum opsonized zymosan was more rapidly inhibited than the fMLP- and PMA-activated pathways, the responses induced by the different stimulators were similarly affected, suggesting a modulation of common components in the activation pathways, possibly protein kinase C or the NADPH-oxidase complex, after administration of low pharmacological doses of glucocorticoids in vivo.
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Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller, Norway.
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003907:Dexamethasone / Q000097:blood / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D007958:Leukocyte Count; D008163:Luminescent Measurements; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008776:Methylprednisolone Hemisuccinate / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010529:Peritoneal Cavity / Q000166:cytology; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D017382:Reactive Oxygen Species; D008776:Methylprednisolone Hemisuccinate; D003907:Dexamethasone