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Activation of peroxisome proliferator-activated receptor γ inhibits IL-1β-induced mPGES-1 expression in human synovial fibroblasts by interfering with Egr-1
Arthritis Res Thervolume 6, Article number: 65 (2004)
Membrane-associated prostaglandin (PG) E synthase-1 (mPGES-1) catalyzes the conversion of PGH2 to PGE2, which plays a critical role in the pathogenesis of arthritis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor and was shown to regulate a number of inflammatory genes in several cell types. In this study, we examined the effect of PPARγ ligands on IL-1β-induced mPGES-1 expression in human synovial fibroblasts.
The PPARγ ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the thiazolidinedione troglitazone (TRO), but not the PPARα ligand Wy14643, dose-dependently suppressed IL-1β-induced PGE2 production, as well as mPGES-1 protein and mRNA expression. 15d-PGJ2 and TRO suppressed IL-1β-induced activation of the mPGES-1 promoter. Overexpression of wild-type PPARγ further enhanced, whereas overexpression of a dominant negative PPARγ alleviated, the suppressive effect of both PPARγ ligands. Furthermore, pretreatment with an antagonist of PPARγ, GW9662, relieved the suppressive effect of PPARγ ligands on mPGES-1 protein expression, suggesting that the inhibition of mPGES-1 expression is mediated by PPARγ.
Previous studies have shown that Egr-1 plays a pivotal role in transactivation of mPGES-1 gene. We demonstrated that PPARγ ligands suppressed Egr-1-mediated induction of the activities of the mPGES-1 promoter and of a synthetic reporter construct containing three tandem repeats of an Egr-1 binding site. Electrophoretic mobility shift and super-shift assays for Egr-1 binding sites in the mPGES-1 promoter showed that both 15d-PGJ2 and TRO suppressed IL-1β-induced DNA binding activity of Egr-1. This occurs without interfering with Egr-1 expression.
These data define mPGES-1 and Egr-1 as novel targets of PPARγ and provide further support for the promising application of PPARγ ligands in the treatment of arthritis.
This work was supported by the Canadian Institutes of Health Research, the Fonds de Recherche en Santé du Québec, Subvention d'Établissement du Jeune Chercheur and the Fonds de la Recherche du Centre de Recherche du Centre hospitalier de l'Université de Montréal.