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.