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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Santini
G
G
Division of Pharmacology, Department of Medicine and Aging, G. D'Annunzio University of Chieti School of Medicine, Italy.
Patrignani
P
P
Sciulli
M G
MG
Seta
F
F
Tacconelli
S
S
Panara
M R
MR
Ricciotti
E
E
Capone
M L
ML
Patrono
C
C
D001172:Arthritis, Rheumatoid / Q000201:enzymology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000494:pharmacology*; D007527:Isoenzymes / Q000097:blood*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D008775:Methylprednisolone / Q000494:pharmacology; D009000:Monocytes / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D003907:Dexamethasone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D006854:Hydrocortisone; D008775:Methylprednisolone