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 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.
Highlights
MPGES-1 is an inducible enzyme that acts downstream of cyclooxygenase (COX) and catalyzes the conversion of prostaglandin (PG) H2 to PGE2 under basal as well as inflammatory conditions
Results showed that under basal conditions, PPAR␥ mRNA and protein levels were significantly higher (p Ͻ 0.05) in the mPGES-1 null mouse embryo fibroblasts (MEFs) compared with their wild type (WT) counterparts
PPAR␥ transcriptional activity was significantly higher (p Ͻ 0.01) in mPGES-1 null MEFs compared with WT MEFs under basal conditions
Summary
MPGES-1 (microsomal PGE synthase-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) and catalyzes the conversion of prostaglandin (PG) H2 to PGE2 under basal as well as inflammatory conditions. 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 decreases proinflammatory PGE2 and up-regulates anti-inflammatory PPAR␥, which has the ability to suppress COX-2 and mPGES-1 expression and PGE2 production. The effects of PGE2 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). MPGES-1 is an attractive target to achieve more specific inhibition of PGE2 production associated with inflammatory disorders while preserving production of other PGs. Specific inhibitors of mPGES-1 are yet not available; studies using mice genetically deficient in mPGES-1 have demonstrated that this enzyme is a key mediator of inflammation, pain, angiogenesis, fever, bone metabolism, and tumorigenesis (14 –17). Previphate dehydrogenase; WT, wild type; RT, reverse transcription; FBS, fetal bovine serum; IL, interleukin; TBS, Tris-buffered saline; MAP, mitogen-activated protein; ELISA, enzyme-linked immunosorbent assay; MEK, MAP kinase/extracellular signal-regulated kinase kinase
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
