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Nanomolar and micromolar effects of 15-deoxy-delta 12,14-prostaglandin J2 on amnion-derived WISH epithelial cells: differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B.

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)-1beta-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 microM), 15d-PGJ(2) inhibited IL-1beta-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-phenyl-benzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-gamma ligand rosiglitazone. At higher concentrations (1-10 microM), 15d-PGJ(2) inhibited IL-1beta-stimulated PGE(2) and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations (1-10 microM) stimulated PGE(2) production in the absence or presence of the dominant-negative PPAR. The PPAR-delta ligand GW501516 also inhibited IL-1beta-stimulated PGE(2) production but only at high concentrations (1 microM). IL-1beta-induced nuclear factor-kappaB (NF-kappaB) DNA binding activity was significantly inhibited by 15d-PGJ(2) (10 microM) and GW501516 (1 microM) but increased with 10 microM 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-kappaB; and 3) rosiglitazone exerts PPAR-independent effects at high concentrations (>1 microM).

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Berry EB,Keelan JA,Helliwell RJ,Gilmour RS,Mitchell MD

doi

10.1124/mol.104.009449

keywords:

subject

Has Abstract

pub_date

2005-07-01 00:00:00

pages

169-78

issue

eissn

0026-895X

issn

1521-0111

pii

mol.104.009449

journal_volume

pub_type

杂志文章

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Nanomolar and micromolar effects of 15-deoxy-delta 12,14-prostaglandin J2 on amnion-derived WISH epithelial cells: differential roles of peroxisome proliferator-activated receptors gamma and delta and nuclear factor kappa B.