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Modulation of Cytokine-Induced Cyclooxygenase 2 Expression by PPARG Ligands Through NFB Signal Disruption in Human WISH and Amnion Cells¹

Department of Obstetrics and Gynecology, Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine,³ Center for Biomedical Engineering,⁴ Dorothy M. Davis Heart and Lung Research Institute and Department of Internal Medicine,⁵ The Ohio State University, Columbus, Ohio 43210

Cyclooxygenase (COX) activity increases in the human amnion in the settings of term and idiopathic preterm labor, contributing to the generation of uterotonic prostaglandins (PGs) known to participate in mammalian parturition. Augmented COX activity is highly correlated with increased COX2 (also known as prostaglandin-endoperoxide synthase 2, PTGS2) gene expression. We and others have demonstrated an essential role for nuclear factor B (NFB) in cytokine-driven COX2 expression. Peroxisome proliferator-activated receptor gamma (PPARG), a member of the nuclear hormone receptor superfamily, has been shown to antagonize NFB activation and inflammatory gene expression, including COX2. We hypothesized that PPARG activation might suppress COX2 expression during pregnancy. Using primary amnion and WISH cells, we evaluated the effects of pharmacological (thiazolidinediones) and putative endogenous (15-deoxy-^12,14-prostaglandin J₂, 15d-PGJ₂) PPARG ligands on cytokine-induced NFB activation, COX2 expression, and PGE₂ production. We observed that COX2 expression and PGE₂ production induced by tumor necrosis factor alpha (TNF) were significantly abrogated by 15d-PGJ₂. The thiazolidinediones rosiglitazone (ROSI) and troglitazone (TRO) had relatively little effect on cytokine-induced COX2 expression except at high concentrations, at which these agents tended to increase COX2 abundance relative to cells treated with TNF alone. Interestingly, treatment with ROSI, but not TRO, led to augmentation of TNF-stimulated PGE₂ production. Mechanistically, we observed that 15d-PGJ₂ markedly diminished cytokine-induced activity of the NFB transcription factor, whereas thiazolidinediones had no discernable effect on this system. Our data suggest that pharmacological and endogenous PPARG ligands use both receptor-dependent and -independent mechanisms to influence COX2 expression.

cytokines, gene regulation, parturition, placenta, pregnancy

² Correspondence: Douglas A. Kniss, Laboratory of Perinatal Research, Department of Obstetrics and Gynecology, The Ohio State University, 5th Floor Means Hall, 1654 Upham Drive, Columbus, OH 43210. FAX: 614 293 5728; kniss.1{at}osu.edu

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