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The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids
Author(s) -
Santini Giovanna,
Patrignani Paola,
Sciulli Maria G.,
Seta Francesca,
Tacconelli Stefania,
Panara Maria R.,
Ricciotti Emanuela,
Capone Marta L.,
Patrono Carlo
Publication year - 2001
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(01)14130-5
Subject(s) - methylprednisolone , monocyte , cyclooxygenase , dexamethasone , lipopolysaccharide , whole blood , in vivo , medicine , endocrinology , radioimmunoassay , glucocorticoid , ex vivo , rheumatoid arthritis , pharmacology , chemistry , in vitro , biology , enzyme , biochemistry , microbiology and biotechnology
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 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 μg/ml) for 24 hours at 37°C, and PGE 2 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. PGE 2 was evaluated by radioimmunoassay. Results Nanomolar concentrations of cortisol, 6‐methylprednisolone, and dexamethasone 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 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 PGE 2 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. Clinical Pharmacology & Therapeutics (2001) 70 , 475–483; doi: 10.1016/S0009‐9236(01)14130‐5