Onapristone (ZK299) blocks the suppressive effect of progesterone, but not that of dexamethasone, on inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages

Suppressive effects of progesterone on inducible nitric oxide synthase (iNOS) protein expression and nitric oxide (NO) production in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS) and the inhibition of the suppressive activity of progesterone by onapristone (ZK299), a synthetic progesterone inhibitor, were studied. Progesterone suppressed dose-dependently LPS-induced NO production by macrophages, and scarcely detectable expression of iNOS was seen in the macrophages. ZK299 liberated the macrophages from the inhibitory effect of progesterone. Although dexamethasone, a synthetic glucocorticoid, can potently suppress LPS-induced NO production by macrophages, ZK299 did not liberate the suppression by dexamethasone, suggesting that these two corticosteroids induce suppression through independent mechanisms. RT–PCR analysis showed that murine macrophages expressed no progesterone-receptor. These findings indicate that the inhibitory effect of progesterone occurs at least on the level of iNOS protein expression in the signaling pathway after the LPS-stimulus. Furthermore, our present data may suggest the existence of a yet unknown type of progesterone-receptor in murine macrophages, the binding to which is responsible for the inhibitory effect of progesterone, or that progesterone may act non-specifically on the macrophages without involvement of any receptor.