Regulation of prostaglandin production in intact fetal membranes by interleukin-1 and its receptor antagonist

Abstract

There is strong evidence for the involvement of inflammatory mediators such as interleukin (IL)-1 in the biochemical mechanisms of parturition. Therefore the effects of the IL-1 family (IL-1α (1 ng/ml), IL-1β (1 ng/ml) and the IL-1 receptor antagonist (IL-1ra) (10 ng/ml)) on the regulation of prostaglandin synthesis in term human fetal membranes were investigated. It was found that, after 4 h of culture, IL-1β increased prostaglandin E2 (PGE2) output approximately twofold. This was associated with both a significant increase in cyclo-oxygenase-2 (COX-2) mRNA levels (approximately fourfold compared with control) and translocation of cytoplasmic phospholipase A2 (cPLA2) from the cytosol to the membrane fraction. IL-1α was less effective than IL-1β at stimulating PGE2 production through similar mechanisms. IL-1ra had no effect on PGE2 output. However, in combination treatments, IL-1ra did not inhibit IL-1α- or IL-1β-stimulated PGE2 output, and increased PGE2 production further compared with IL-1β alone. IL-1ra decreased IL-1β-induced COX-2 mRNA expression by about half and significantly increased cPLA2 protein levels, as detected by immunoblotting, when used alone and together with IL-1β. These results suggest that IL-1ra has partial agonist properties when used together with IL-1α and IL-1β in fetal membranes by increasing cPLA2 protein levels, which leads to an increase in the production of prostaglandins.