Nanomolar and micromolar effects of 15-deoxy-Delta(12,14)-prostaglandin J(2) on amnion-derived WISH epithelial cells: Differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B

Berry, Elicia B. E., Keelan, Jeffrey A., Helliwell, Rachel J. A., Gilmour, R. Stewart and Mitchell, Murray D. (2005) Nanomolar and micromolar effects of 15-deoxy-Delta(12,14)-prostaglandin J(2) on amnion-derived WISH epithelial cells: Differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B. Molecular Pharmacology, 68 1: 169-178. doi:10.1124/mol.104.009449


Author Berry, Elicia B. E.
Keelan, Jeffrey A.
Helliwell, Rachel J. A.
Gilmour, R. Stewart
Mitchell, Murray D.
Title Nanomolar and micromolar effects of 15-deoxy-Delta(12,14)-prostaglandin J(2) on amnion-derived WISH epithelial cells: Differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
Publication date 2005-07
Sub-type Article (original research)
DOI 10.1124/mol.104.009449
Volume 68
Issue 1
Start page 169
End page 178
Total pages 10
Place of publication Bethesda, MD U.S.A.
Publisher American Society for Pharamacology and Experimental Therapeutics
Language eng
Subject 0604 Genetics
1103 Clinical Sciences
Formatted abstract
15-Deoxy Δ12,14-prostaglandin J2 (15d-PGJ 2), 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 (<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 (<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-PGJ 2 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 (>1 μM). Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.
Keyword Human Gestational Tissues
Nitric-oxide Synthase
JEG3 Choriocarcinpma Cells
Ppar-gamma
Cyclopentenone Prostaglandins
Cyclooxygenase-2 Expression
Human Trophoblast
Feedback-control
Mesangial Cells
Human-pregnancy
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Centre for Clinical Research Publications
 
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Created: Thu, 26 Aug 2010, 12:46:01 EST