Microsomal Prostaglandin E Synthase-1 Deficiency Is Associated with Elevated Peroxisome Proliferator-activated Receptor γ

Abstract

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 ␥ (PPAR␥) 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 PPAR␥ through a cAMP-independent pathway involving phosphatidylinositol 3-kinase and Akt signaling. Using specific PPAR␥ agonist (rosiglitazone), PPAR␥ ligand (15-deoxy-⌬12,14-PGJ 2 ), and PPAR␥ inhibitor (GW9662), we confirm that activation of PPAR␥ blocks interleukin-1␤-induced up-regulation of COX-2, mPGES-1, and their derived PGE 2 . Furthermore, we demonstrate that up-regulation of PPAR␥ upon genetic deletion of mPGES-1 is responsible for reduced COX-2 expression under basal as well as interleukin-1␤-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 PPAR␥, 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. Prostaglandins (PGs)2 are formed by metabolism of arachidonic acid by cyclooxygenases (COX) to generate an intermediate substrate, PGH 2 , which is further metabolized by terminal synthases to generate specific PGs (1, 2). mPGES-1, originally known as microsomal glutathione S-transferase 1-like 1 (MGST1-L1), is an inducible enzyme that acts downstream of COX and specifically catalyzes the conversion of PGH 2 to PGE 2 (3), most prominently in inflammatory conditions (4, 5). However, we have recently shown that mPGES-1 is critical for PGE 2 production under basal as well as inflammatory conditions (6).mPGES-1 is coordinately induced with COX-2 by inflammatory stimuli in a variety of cells and tissues (4, 7). PGE 2 is the most abundant PG associated with inflammatory conditions, and overproduction of PGE 2 coincides with increased COX-2 and mPGES-1 expression (4, 7). PGE 2 exerts the majority of its actions through a family of G protein-coupled receptors, including EP1, EP2, EP3, and EP4 (8). The effects of PGE 2 via these receptors are mediated through various downstream signaling pathways, including cAMP-dependent protein kinase, mitogen-activated protein kinase (MAP kinase), phosphatidylinositol 3-kinase (PI 3-kinase), and Akt (8 -10).Inhibition of PGE 2 production and action is associated with reduction of the pain and inflammation associated with a wide variety of diseases. Nonselective and COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) block PGE 2 production by inhibiting the activity of COX and are extensively used to treat arthritis a...

Coordinate Functional Regulation between Microsomal Prostaglandin E Synthase-1 (mPGES-1) and Peroxisome Proliferator-activated Receptor γ (PPARγ) in the Conversion of White-to-brown Adipocytes

“…On the other hand, exogenous PGE 2 was able to suppress PPAR␥ expression, whereas opposite effects were seen after inhibition of endogenous PGE 2 biosynthesis in adipose tissue from WT mice. The existence of this negative regulatory loop is consistent with previous studies showing that pre-adipocytes stably transfected with either COX-1 or COX-2 had lower PPAR␥ expression (16) and that mice genetically deficient for mPGES-1 had basal elevations in PPAR␥ expression and transcriptional activity (17). Moreover, our results are suggestive of the existence of a positive feedback loop between PGE 2 and local COX-2 and mPGES-1 expression in adipose tissue (Fig.…”

“…For example, PGE 2 is recognized as a negative regulator of WAT lipolysis and adipocyte development (14,15), and preadipocytes stably transfected with either COX-1 or COX-2 show lower PPAR␥ expression (16). Consistent with this view, mice genetically deficient for mPGES-1 show basal elevations in PPAR␥ expression and transcriptional activity (17). However, more recent studies have shown that transgenic mice overexpressing COX-2 do not exhibit changes in PPAR␥ expression in adipose tissues (18), although PPAR␥ expression has been shown to be significantly reduced in adipose tissue from COX-2-deficient mice (19).…”

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

“…Surprisingly, mPGES-1 null iMACs do not make similar amounts of MMP3 as wildtype cells when the PGE 2 signal is provided directly with either exogenous PGE 2 or forskolin. This difference could be due to peroxisome proliferator-activated receptor g (PPARg) differences (16).…”

“…mPGES-1-deficient mice develop normally and do not differ from wild-type mice with respect to general appearance, behavior, and longevity (15)(16)(17)(18). In a collagen-induced arthritis model, mPGES-1-deficient mice exhibit significantly less severe and less common arthritis features compared with wild-type mice.…”

Prostaglandin E2signals white-to-brown adipogenic differentiation

“…44 This finding is consistent with the observation that mice genetically deficient for mPGES-1 show basal elevations in PPARg expression and transcriptional activity of this nuclear receptor. 45 In contrast, PPARg appears to be downregulated in adipose tissue from COX-2 deficient mice, which show an attenuation in adipocyte differentiation. 46 Also, Kim and collaborators recently described that a COX-2 dependent metabolism of 20-hydroxy-eicosatetraenoic acid (20-HETE) induces PPARg and the adipogenic program in mesenchymal stem cell-derived adipocytes.…”