The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisoland synthetic glucocorticoids

Background. We studied the concentration dependence of the inhibitory effec ts of cortisol, 6-methylprednisolone, and dexamethasone on cyclooxygenase-2 (COX-2) expression and activity in human monocytes in response to lipopoly saccharide (LPS) in vitro. Moreover, we characterized the time and dose dep endence of the inhibitory effects of 6-methylprednisolone, administered to healthy subjects, on LPS-inducible prostaglandin E-2 (PGE(2)) biosynthesis in whole blood ex vivo. Methods. Heparinized whole-blood samples obtained from healthy subjects and patients with rheumatoid arthritis were incubated with LPS (10 mug/ml) for 24 hours at 37 degreesC, and PGE(2) was measured in plasma as an index of monocyte COX-2 activity. Comparative experiments were performed in LPS-stim ulated isolated monocytes. The levels of COX-2-like immunoreactivity in mon ocyte lysates were measured by a specific Western blot technique. PGE(2) wa s evaluated by radioimmunoassay. Results: Nanomolar concentrations of cortisol, 6-methylprednisolone, and de xamethasone suppressed LPS-induced PGE(2) 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 o f 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 s amples obtained from patients with rheumatoid arthritis treated with compar able maintenance doses of glucocorticoids produced significantly lower leve ls of LPS-inducible PGE, than were found in untreated patients. Conclusions: Therapeutic plasma levels of synthetic glucocorticoids down-re gulate inducible prostanoid biosynthesis in circulating monocytes. This eff ect may represent a readily measurable surrogate marker of their clinical e fficacy for dose-finding studies.