Signal pathways involved in the regulation of prostaglandin E synthase-1 in human gingival fibroblasts

Microsomal prostaglandin E synthase-1 (mPGES- 1) is the terminal enzyme regulating the synthesis of prostaglandin E-2 (PGE(2)) in inflammatory conditions. In this study we investigated the regulation of mPGES-1 in gingival fibroblasts stimulated with the inflammatory mediators interleukin-1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha). The results showed that IL-1 beta and TNF alpha induce the expression of mPGES-1 without inducing the expression of early growth response factor-1 (Egr-1). Treatment of the cells with the PLA(2) inhibitor 4-bromophenacyl bromide (BPB) decreased the cytokine-induced mPGES-1 expression accompanied by decreased PGE2 production whereas the addition of arachidonic acid (AA) upregulated mPGES-1 expression and PGE2 production. The protein kinase C (PKC) activator PMA did not upregulate the expression of mPGES-1 in contrast to COX-2 expression and PGE(2) production. In addition, inhibitors of PKC, tyrosine and p38 MAP kinase markedly decreased the cytokine-induced PGE2 production but not mPGES- I expression. Moreover, the prostaglandin metabolites PGE(2) and PGF(2 alpha) induced mPGES-1 expression as well as upregulated the cytokine-induced mPGES-1 expression indicating positive feedback regulation of mPGES-1 by prostaglandin metabolites. The peroxisome proliferator-activated rcceptor-gamma (PPAR-gamma) ligand, 15-deoxy-Delta 12,14-prostaglandin J(2) (15d-PGJ(2)), decreased mPGES-1 expression but not COX-2 expression or PGE2 production. The results indicate that the inflammatory-induced mPGES- I expression is regulated by PLA2 and 15d-PGJ(2) but not by PKC, tyrosine kinase or p38 MAP kinase providing new insights into the regulation of mPGES-1. (c) 2006 Elsevier Inc. All rights reserved.