TY - JOUR T1 - Nanomolar and Micromolar Effects of 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub> on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB JF - Molecular Pharmacology JO - Mol Pharmacol SP - 169 LP - 178 DO - 10.1124/mol.104.009449 VL - 68 IS - 1 AU - Elicia B. E. Berry AU - Jeffrey A. Keelan AU - Rachel J. A. Helliwell AU - R. Stewart Gilmour AU - Murray D. Mitchell Y1 - 2005/07/01 UR - http://molpharm.aspetjournals.org/content/68/1/169.abstract N2 - 15-Deoxy Δ12,14-prostaglandin J2 (15d-PGJ2), an activator of peroxisome proliferator-activated receptor (PPAR)-γ and -δ, 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 (&lt;3 h) effects of 15d-PGJ2 with rosiglitazone (PPAR-γ ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516) (PPAR-δ ligand) on interleukin (IL)-1β–induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ2 exerts differential effects depending on concentration. At low concentrations (&lt;0.1 μM), 15d-PGJ2 inhibited IL-1β–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-γ inhibitor [2-chloro-5-nitro-N-phenyl-benzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-γ ligand rosiglitazone. At higher concentrations (1–10 μM), 15d-PGJ2 inhibited IL-1β–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-δ ligand GW501516 also inhibited IL-1β–stimulated PGE2 production but only at high concentrations (1 μM). IL-1β–induced nuclear factor-κB (NF-κB) 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-γ signaling pathway; b) at higher concentrations, its actions are mediated most likely through other pathways such as activation of PPAR-δ and/or inhibition of NF-κB; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations (&gt;1 μM). ER -