Received for publication November 22, 2004.
Revised April 5, 2005.
Accepted for publication April 7, 2005.

Nanomolar and micromolar effects of 15-deoxy-^12,14-Prostaglandin J₂ on amnion-derived WISH epithelial cells: differential roles of PPAR-, - and NF-B

Abstract

15-deoxy ^12,14-prostaglandin J₂ (15d-PGJ₂), an activator of PPAR- and -, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, pro-inflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and onset of labor. We investigated and compared the early (<3 hours) effects of 15d-PGJ₂ with rosiglitazone (PPAR- ligand) and GW501516 (PPAR- ligand), on IL-1- induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ₂ exerted a high and low concentration differential effect. At low concentrations (<0.1 µM), 15d-PGJ₂ inhibited IL-1-stimulated PGE₂, but not cytokine (IL-6/IL-8) or COX-2 expression. This effect was attenuated by a PPAR- inhibitor (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, 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 NF-B DNA binding activity was significantly inhibited by 15d-PGJ₂ (10 µM) and GW501516 (1 µM). We conclude that a) 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; c) rosiglitazone exerts PPAR-independent effects at high concentrations (>1 µM).

Key words: Prostanoid, Interleukins, PPARs, NFkappaB, Cyclooxygenases

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