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

• Published in: Cellular signalling 2006-12, Vol.18 (12), p.2131-2142
• Main Authors: Yucel-Lindberg, Tülay, Olsson, Tove, Kawakami, Tomomi
• Format: Article
• Language: English
• Subjects: Arachidonic Acid - pharmacology; Blotting, Western; Cells, Cultured; Child; Dinoprost - pharmacology; Dinoprostone - biosynthesis; Dinoprostone - pharmacology; Dose-Response Relationship, Drug; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation - drug effects; Gingiva - cytology; Gingiva - drug effects; Gingiva - metabolism; Gingival fibroblasts; Humans; Imidazoles - pharmacology; Indoles - pharmacology; Inflammatory mediators; Interleukin-1beta - pharmacology; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Maleimides - pharmacology; Medicin och hälsovetenskap; mPGES-1; NF-kappa B - metabolism; p38 MAP kinase; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; PGE 2; PGF 2α; PKC; PPARγ; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Prostaglandin-E Synthases; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyridines - pharmacology; Quinazolines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2006.04.003

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 β (IL-1β) and tumour necrosis factor α (TNFα). The results showed that IL-1β and TNFα 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 PGE 2 production whereas the addition of arachidonic acid (AA) upregulated mPGES-1 expression and PGE 2 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 PGE 2 production but not mPGES-1 expression. Moreover, the prostaglandin metabolites PGE 2 and PGF 2α 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 receptor-γ (PPARγ) ligand, 15-deoxy-Δ12,14-prostaglandin J 2 (15d-PGJ 2), decreased mPGES-1 expression but not COX-2 expression or PGE 2 production. The results indicate that the inflammatory-induced mPGES-1 expression is regulated by PLA 2 and 15d-PGJ 2 but not by PKC, tyrosine kinase or p38 MAP kinase providing new insights into the regulation of mPGES-1.