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

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-1 alpha (1 ng/ml), IL-1 beta (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-1 beta increased prostaglandin E-2 (PGE(2)) 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 A(2) (cPLA(2)) from the cytosol to the membrane fraction. IL-1 alpha was less effective than IL-1 beta at stimulating PGE(2) production through similar mechanisms. IL-1ra had no effect on PGE(2) output. However, in combination treatments, IL-1ra did not inhibit IL1 alpha- or IL-1 beta-stimulated PGE(2) output, and increased PGE(2) production further compared with IL-1 beta alone. IL-1ra decreased IL-1 beta-induced COX-2 mRNA expression by about half and significantly increased cPLA(2) protein levels, as detected by immunoblotting, when used alone and together with IL-1 beta. These results suggest that IL-1ra has partial agonist properties when used together with IL-1 alpha and IL-1 beta in fetal membranes by increasing cPLA(2) protein levels, which leads to an increase in the production of prostaglandins.