Deletion of Microsomal Prostaglandin E2 (PGE2) Synthase-1 Reduces Inducible and Basal PGE2 Production and Alters the Gastric Prostanoid Profile

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible protein recently shown to be an important source of inflammatory PGE2. Here we have used mPGES-1 wild type, heterozygote, and null mice to assess the impact of reduction or absence mPGES-1 protein on the production of PGE2 and other pro...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-05, Vol.279 (22), p.23229-23237
Main Authors: Boulet, Louise, Ouellet, Marc, Bateman, Kevin P., Ethier, Diane, Percival, M. David, Riendeau, Denis, Mancini, Joseph A., Méthot, Nathalie
Format: Article
Language:English
Subjects:
Animals
Cyclooxygenase 1
Dinoprostone - biosynthesis
Gastric Mucosa - metabolism
Gene Deletion
Gene Expression Regulation, Enzymologic
Intramolecular Oxidoreductases - antagonists & inhibitors
Intramolecular Oxidoreductases - biosynthesis
Intramolecular Oxidoreductases - genetics
Isoenzymes - metabolism
Membrane Proteins
Mice
Microsomes - enzymology
Organ Specificity
Prostaglandin-E Synthases
Prostaglandin-Endoperoxide Synthases - metabolism
Prostaglandins - metabolism
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Summary:Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible protein recently shown to be an important source of inflammatory PGE2. Here we have used mPGES-1 wild type, heterozygote, and null mice to assess the impact of reduction or absence mPGES-1 protein on the production of PGE2 and other prostaglandins in lipopolysaccharide (LPS)-treated macrophages and mice. Thioglycollate-elicited peritoneal macrophages with mPGES-1 deficiency were found to lose their ability to produce PGE2 upon LPS stimulation. Resident mPGES-1-/- peritoneal macrophages exhibited severely impaired PGE2-releasing activity but retained some LPS-inducible PGE2 production capacity. Both macrophage types showed a 50% decrease in PGE2 production with removal of one copy of the mPGES-1 gene. In vivo, mPGES-1 deletion abolished the LPS-stimulated production of PGE2 in spleen, kidney, and brain. Surprisingly, lack of mPGES-1 activity resulted in an 80-90% decrease in basal, cyclooxygenase-1 (COX-1)-dependent PGE2 production in stomach and spleen, and a 50% reduction in brain and kidney. Other prostaglandins (thromboxane B2, PGD2, PGF2α, and 6-keto-PGF1α) were significantly elevated in stomachs of mPGES-1-null mice but not in other tissues. Examination of mRNA for several terminal prostaglandin synthases did not reveal changes in expression levels associated with mPGES-1 deficiency, indicating that gastric prostaglandin changes may be due to shunting of cyclooxygenase products to other terminal synthases. These data demonstrate for the first time a dual role for mPGES-1 in both inflammatory and COX-1-mediated PGE2 production and suggest an interdependence of prostanoid production with tissue-specific alterations of prostaglandin levels in the absence of mPGES-1.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M400443200