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J. Biol. Chem., Vol. 282, Issue 8, 5356-5366, February 23, 2007

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

REGULATION BY PROSTAGLANDIN E₂ VIA THE PHOSPHATIDYLINOSITOL 3-KINASE AND AKT PATHWAY^*

Mohit Kapoor, Fumiaki Kojima, Min Qian, Lihua Yang, and Leslie J. Crofford¹

From the Department of Internal Medicine, Rheumatology Division, University of Kentucky, Lexington, Kentucky 40536 and the Department of Ophthalmology and Visual Sciences, Division of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109

mPGES-1 (microsomal PGE synthase-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin (PG) H₂ to PGE₂ 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 PGE₂. We further show that basal mPGES-1-derived PGE₂ 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-PGJ₂), and PPAR inhibitor (GW9662), we confirm that activation of PPAR blocks interleukin-1-induced up-regulation of COX-2, mPGES-1, and their derived PGE₂. 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 PGE₂ but also up-regulates anti-inflammatory PPAR, which has the ability to suppress COX-2 and mPGES-1 expression and PGE₂ production. Thus, mPGES-1 inhibition may limit inflammation by multiple mechanisms and is a potential therapeutic target.

Received for publication, October 30, 2006 , and in revised form, December 22, 2006.

^* This work was supported by the NIAMS Grant R01 AR 049010 from the National Institutes of Health and an Arthritis Foundation Biomedical Sciences grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, Rheumatology Division, Rm. J-509, KY Clinic, University of Kentucky, Lexington, KY 40536-0284. Tel.: 859-323-4939; Fax: 859-257-8258; E-mail: lcrofford{at}uky.edu.

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