Regulation of proinflammatory cytokines in human gestational tissues by peroxisome proliferator-activated receptor-gamma: effect of 15-deoxy-Delta(12,14)-PGJ(2) and troglitazone.

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-dependent nuclear receptor that is essential for murine placental development and trophoblast differentiation. In nonreproductive tissues, PPAR-gamma regulates the formation of proinflammatory cytokines. Evidence suggests that many of the observed anti-inflammatory effects of PPAR-gamma are in part caused by antagonizing the activities of the transcription factors, including nuclear factor-kappa B. The aim of this study was to elucidate whether natural [15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2))] and synthetic (troglitazone) PPAR-gamma ligands regulate the secretion of IL-6, IL-8, and TNF-alpha from human intrauterine tissues. Human placenta, amnion, and choriodecidual tissues were incubated in the presence of 10 micro g/ml lipopolysaccharide in the absence (control) or presence of 30 micro M 15d-PGJ(2) (n = 6 independent placenta) or troglitazone (n = 6 independent placentas). After a 6-h incubation, the incubation medium was collected and the release of IL-6, IL-8, and TNF-alpha was quantified by ELISA. Treatment of placental, amnion, and choriodecidual tissues with both 15d-PGJ(2) and troglitazone significantly reduced the release of lipopolysaccharide-stimulated IL-6, IL-8, and TNF-alpha (t test, P < 0.05). Gel shift analyses demonstrated that 15d-PGJ(2), but not troglitazone, suppressed nuclear factor-kappa B DNA-binding activity. The data presented in this study demonstrate that the formation of proinflammatory mediators can be modulated by currently available therapeutic agents and may therefore be of therapeutic potential in human labor.