Abstract
Membrane-associated prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes the conversion of PGH(2) to PGE(2), which contributes to many biological processes. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. Here, we examined the effect of PPARgamma ligands on interleukin-1beta (IL-1beta)-induced mPGES-1 expression in human synovial fibroblasts. PPARgamma ligands 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)) and the thiazolidinedione troglitazone (TRO), but not PPARalpha ligand Wy14643, dose-dependently suppressed IL-1beta-induced PGE(2) production, as well as mPGES-1 protein and mRNA expression. 15d-PGJ(2) and TRO suppressed IL-1beta-induced activation of the mPGES-1 promoter. Overexpression of wild-type PPARgamma further enhanced, whereas overexpression of a dominant negative PPARgamma alleviated, the suppressive effect of both PPARgamma ligands. Furthermore, pretreatment with an antagonist of PPARgamma, GW9662, relieves the suppressive effect of PPARgamma ligands on mPGES-1 protein expression, suggesting that the inhibition of mPGES-1 expression is mediated by PPARgamma. We demonstrated that PPARgamma 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. The suppressive effect of PPARgamma ligands was enhanced in the presence of a PPARgamma expression plasmid. Electrophoretic mobility shift and supershift assays for Egr-1 binding sites in the mPGES-1 promoter showed that both 15d-PGJ(2) and TRO suppressed IL-1beta-induced DNA-binding activity of Egr-1. These data define mPGES-1 and Egr-1 as novel targets of PPARgamma and suggest that inhibition of mPGES-1 gene transcription may be one of the mechanisms by which PPARgamma regulates inflammatory responses.
Highlights
Prostaglandin (PG)1 E2 is an important modulator of many physiological and pathophysiological conditions, including cell growth, vascular homeostasis, inflammation, immune regulation, cancer, and arthritis [1, 2]
Effect of Peroxisome proliferator-activated receptors (PPARs) Ligands on IL-1-induced PGE2 Production and Membrane-associated prostaglandin (PG) E2 synthase-1 (mPGES-1) Protein Expression in HSF—We initially examined the effect of three distinct classes of PPAR ligands on IL-1-induced PGE2 production in HSF: 15d-PGJ2 and TRO, natural and synthetic PPAR␥ activators, respectively, and Wy14643, a selective PPAR␣ activator
To confirm the involvement of PPAR␥ in the suppressive effects of 15d-PGJ2 and TRO on IL-1-induced mPGES-1 expression, we examined the action of GW9662, a selective and irreversible PPAR␥ antagonist
Summary
Prostaglandin (PG)1 E2 is an important modulator of many physiological and pathophysiological conditions, including cell growth, vascular homeostasis, inflammation, immune regulation, cancer, and arthritis [1, 2]. PPAR␥ ligands, 15d-PGJ2 and TRO, suppressed IL-1-induced mPGES-1 protein expression in a dose-dependent manner (Fig. 2, A and B). The concentrations of 15d-PGJ2 and TRO that inhibited IL-1-induced mPGES-1 expression and PGE2 production had no effect on cell viability as determined by Trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays (data not shown).
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