The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids

• Published in: Clinical pharmacology and therapeutics Vol. 70; no. 5; p. 475
• Main Authors: Santini, G, Patrignani, P, Sciulli, M G, Seta, F, Tacconelli, S, Panara, M R, Ricciotti, E, Capone, M L, Patrono, C
• Format: Journal Article
• Language: English
• Published: United States 01.11.2001
• Subjects: Arthritis, Rheumatoid - enzymology; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dexamethasone - pharmacology; Dinoprostone - biosynthesis; Glucocorticoids - pharmacology; Humans; Hydrocortisone - blood; Hydrocortisone - pharmacology; Isoenzymes - blood; Lipopolysaccharides - pharmacology; Membrane Proteins; Methylprednisolone - pharmacology; Monocytes - enzymology; Prostaglandin-Endoperoxide Synthases - blood
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(01)14130-5

We studied the concentration dependence of the inhibitory effects of cortisol, 6-methylprednisolone, and dexamethasone on cyclooxygenase-2 (COX-2) expression and activity in human monocytes in response to lipopolysaccharide (LPS) in vitro. Moreover, we characterized the time and dose dependence of the inhibitory effects of 6-methylprednisolone, administered to healthy subjects, on LPS-inducible prostaglandin E2 (PGE2) biosynthesis in whole blood ex vivo. Heparinized whole-blood samples obtained from healthy subjects and patients with rheumatoid arthritis were incubated with LPS (10 microg/ml) for 24 hours at 37 degrees C, and PGE2 was measured in plasma as an index of monocyte COX-2 activity. Comparative experiments were performed in LPS-stimulated isolated monocytes. The levels of COX-2-like immunoreactivity in monocyte lysates were measured by a specific Western blot technique. PGE2 was evaluated by radioimmunoassay. Nanomolar concentrations of cortisol, 6-methylprednisolone, and dexamethasone suppressed LPS-induced PGE2 biosynthesis both in whole blood and in isolated monocytes in vitro with relative potencies similar to those reported for their anti-inflammatory effects in vivo. The administration of single oral doses (4, 8, or 16 mg) of 6-methylprednisolone caused a dose- and time-dependent inhibition of whole-blood COX-2 activity. Whole-blood samples obtained from patients with rheumatoid arthritis treated with comparable maintenance doses of glucocorticoids produced significantly lower levels of LPS-inducible PGE2 than were found in untreated patients. Therapeutic plasma levels of synthetic glucocorticoids down-regulate inducible prostanoid biosynthesis in circulating monocytes. This effect may represent a readily measurable surrogate marker of their clinical efficacy for dose-finding studies.