Activation of peroxisome proliferator-activated receptor γ inhibits IL-1β-induced mPGES-1 expression in human synovial fibroblasts by interfering with Egr-1

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-Δ^12,14-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.