mPGES-1 (microsomal PGE synthase-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG) H(2) to PGE(2) under basal as well as inflammatory conditions. In this study, using mouse embryo fibroblasts (MEFs) isolated from mice genetically deficient for the mPges-1 gene, we show basal elevation of peroxisome proliferator-activated receptor gamma (PPARgamma) expression (protein and mRNA) and transcriptional activity associated with reduced basal PGE(2). We further show that basal mPGES-1-derived PGE(2) suppresses the expression of PPARgamma through a cAMP-independent pathway involving phosphatidylinositol 3-kinase and Akt signaling. Using specific PPARgamma agonist (rosiglitazone), PPARgamma ligand (15-deoxy-Delta12,14-PGJ(2)), and PPARgamma inhibitor (GW9662), we confirm that activation of PPARgamma blocks interleukin-1beta-induced up-regulation of COX-2, mPGES-1, and their derived PGE(2). Furthermore, we demonstrate that up-regulation of PPARgamma upon genetic deletion of mPGES-1 is responsible for reduced COX-2 expression under basal as well as interleukin-1beta-stimulated conditions. This study provides evidence for the first time that mPGES-1 deletion not only decreases proinflammatory PGE(2) but also up-regulates anti-inflammatory PPARgamma, which has the ability to suppress COX-2 and mPGES-1 expression and PGE(2) production. Thus, mPGES-1 inhibition may limit inflammation by multiple mechanisms and is a potential therapeutic target.