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Nanomolar and Micromolar Effects of 15-Deoxy-^12,14-prostaglandin J₂ on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors and and Nuclear Factor B

Liggins Institute (E.B.E.B., J.A.K., R.S.G., M.D.M.), Departments of Pharmacology & Clinical Pharmacology (J.A.K., M.D.M.) and National Research Centre for Growth and Development and Anatomy with Radiology (R.J.A.H.), University of Auckland, Faculty of Medical & Health Sciences, Auckland, New Zealand

15-Deoxy ^12,14-prostaglandin J₂ (15d-PGJ₂), an activator of peroxisome proliferator-activated receptor (PPAR)- and -, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and the onset of labor. We investigated and compared the early (<3 h) effects of 15d-PGJ₂ with rosiglitazone (PPAR- ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516) (PPAR- ligand) on interleukin (IL)-1–induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ₂ exerts differential effects depending on concentration. At low concentrations (<0.1 µM), 15d-PGJ₂ inhibited IL-1–stimulated prostaglandin E₂ (PGE₂) but not cytokine (IL-6/IL-8) production or cyclooxygenase-2 (COX-2) expression. This effect was attenuated by a PPAR- inhibitor [2-chloro-5-nitro-N-phenyl-benzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR- ligand rosiglitazone. At higher concentrations (1–10 µM), 15d-PGJ₂ inhibited IL-1–stimulated PGE₂ and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations (1–10 µM) stimulated PGE₂ production in the absence or presence of the dominant-negative PPAR. The PPAR- ligand GW501516 also inhibited IL-1–stimulated PGE₂ production but only at high concentrations (1 µM). IL-1–induced nuclear factor-B (NF-B) DNA binding activity was significantly inhibited by 15d-PGJ₂ (10 µM) and GW501516 (1 µM) but increased with 10 µM rosiglitazone. We conclude that 1) at low concentrations, 15d-PGJ₂ acts through a PPAR- signaling pathway; b) at higher concentrations, its actions are mediated most likely through other pathways such as activation of PPAR- and/or inhibition of NF-B; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations (>1 µM).

Address correspondence to: Prof. Murray Mitchell, Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: m.mitchell{at}auckland.ac.nz

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