Nanomolar and Micromolar Effects of 15-Deoxy-Δ12,14-prostaglandin J2 on Amnion-Derived WISH Epithelial Cells: Differential Roles of Peroxisome Proliferator-Activated Receptors γ and δ and Nuclear Factor κB

E.B.E. Berry, Jeffrey Keelan, R.J.A. Helliwell, R.S. Gilmour, M.D. Mitchell

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    Abstract

    15-Deoxy Delta(12,14)- prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, 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-PGJ(2) with rosiglitazone (PPAR-gamma ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)- methylsulfanyl) phenoxy-acetic acid (GW501516) (PPAR-delta ligand) on interleukin (IL)-1 beta-induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ(2) exerts differential effects depending on concentration. At low concentrations (<0.1 mu M), 15d-PGJ(2) inhibited IL-1 beta stimulated prostaglandin E-2 (PGE(2)) but not cytokine (IL-6/IL-8) production or cyclooxygenase-2 (COX-2) expression. This effect was attenuated by a PPAR-gamma inhibitor [2-chloro-5-nitro-N-phenylbenzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-gamma ligand rosiglitazone. At higher concentrations (1 - 10 mu M), 15d-PGJ(2) inhibited IL-1 beta-stimulated PGE(2) and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations ( 1 - 10 mu M) stimulated PGE(2) production in the absence or presence of the dominant-negative PPAR. The PPAR-delta ligand GW501516 also inhibited IL-1 beta-stimulated PGE(2) production but only at high concentrations (1 mu M). IL-1 beta-induced nuclear factor-kappa B (NF-kappa B) DNA binding activity was significantly inhibited by 15d-PGJ(2) ( 10 mu M) and GW501516 ( 1 mu M) but increased with 10 mu M rosiglitazone. We conclude that 1) at low concentrations, 15d-PGJ(2) acts through a PPAR-gamma signaling pathway; b) at higher concentrations, its actions are mediated most likely through other pathways such as activation of PPAR-delta and/or inhibition of NF-kappa B; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations ( >1 mu M).
    Original languageEnglish
    Pages (from-to)169-178
    JournalMolecular Pharmacology
    Volume68
    Issue number1
    DOIs
    Publication statusPublished - 2005

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