Antiinflammatory effects of the cyclopentenone isoprostane 15-A2-IsoP in human gestational tissues

Proinflammatory prostaglandins and cytokines are involved in the initiation of human labor and delivery. Although cyclopentenone prostaglandins regulate the formation of these prolabor mediators via nuclear factor-kappa B (NF-kappa B) and/or peroxisome proliferator-activated receptor-gamma, recent evidence suggests that they do not exist in vivo. Cyclopentenone isoprostanes (IsoPs), which are highly reactive structural isomers of bioactive cyclopentenone Prostaglandins, do exist physiologically and have been shown to inhibit the inflammatory response in macrophages. Therefore the aim of this study was to determine the effect of the synthetic cyclopenterione IosP 15-A(2)-IsoP on the expression of prolabor mediators in human gestational tissues. Human placenta and gestational membranes (n = 5) were incubated in the absence or presence of 12.5, 25, and 50 mu M 15-A(2)-IsoP With 10 mu g/ml lipopolysaccharide (LPS). Treatment of placenta and fetal membranes with 15-A(2)-IsoP caused a dose-dependent decrease in LPS-stimulated release of the cytokines IL-1 beta, IL-6, IL-8, and TNF-alpha and the Prostaglandins PGE(2) and PGF(2)alpha. NF-kappa B p65 UNA binding activity was significantly inhibited by treatment with 50 mu M 15-A(2)-IsoP. Collectively, these data suggest that 15-A(2)-IsoP exhibits antiinflammatory properties via antagonism of NF-kappa B activity. Cyclopentenone IsoPs may serve as negative feedback regulators of the inflammatory response in human gestational tissues. Crown Copyright (c) 2007 Published by Elsevier Inc. All rights reserved.