The regulation of prostaglandin output from term intact fetal membranes by anti-inflammatory cytokines

Abstract

Prostaglandins are some of the main mediators which control parturition, and their production by intrauterine tissues can be up-regulated by pro- inflammatory cytokines. Anti-inflammatory cytokines may oppose these effects, and in this study we have investigated how two such cytokines affected fetal membrane function. Interleukin-10 (IL-10) inhibited the output of prostaglandin E2 (PGE2) from intact fetal membranes under basal and lipopolysaccharide (LPS)-stimulated conditions, and there was a parallel decrease in the expression of mRNA for COX-2. IL-10 also inhibited the production of interleukin-1β (IL-1β) and the expression of mRNA for IL-1β, indicating that this cytokine has a broad anti-inflammatory effect. Transforming growth factor-β1 (TGF-β1), which is generally considered to be anti-inflammatory had opposite effects on PGE2 production, in that it increased the output of PGE2 for up to 8 hr. TGF-β1 increased levels of type-2 cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2) protein, and also activated the cPLA2 enzyme present; the profile of effects is similar to that of the pro-inflammatory cytokine IL-1β, and was not expected. Combinations of TGF-β1 with IL-1β also increased PGE2 output and caused appropriate changes in prostaglandin pathway enzymes, whereas TGF-β1 and IL-1α had more limited effects. Further studies are needed to establish the physiological significance of these findings, but TGF-β1 does not seem to act as an inhibitory cytokine in intact fetal membranes at term.