Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible protein recently shown to be an important source of inflammatory PGE 2 . 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 PGE 2 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 PGE 2 upon LPS stimulation. Resident mPGES-1 ؊/؊ peritoneal macrophages exhibited severely impaired PGE 2 -releasing activity but retained some LPS-inducible PGE 2 production capacity. Both macrophage types showed a 50% decrease in PGE 2 production with removal of one copy of the mPGES-1 gene. In vivo, mPGES-1 deletion abolished the LPS-stimulated production of PGE 2 in spleen, kidney, and brain. Surprisingly, lack of mPGES-1 activity resulted in an 80 -90% decrease in basal, cyclooxygenase-1 (COX-1)-dependent PGE 2 production in stomach and spleen, and a 50% reduction in brain and kidney. Other prostaglandins (thromboxane B 2 , PGD 2 , PGF 2␣ , and 6-keto-PGF 1␣ ) 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 PGE 2 production and suggest an interdependence of prostanoid production with tissue-specific alterations of prostaglandin levels in the absence of mPGES-1.
Prostaglandins (PG)1 are lipid metabolites of arachidonic acid that are synthesized by a two-step reaction catalyzed by a cyclooxygenase and a terminal prostaglandin synthase. The cyclooxygenase product PGH 2 serves as common precursor to all five major prostanoids (TXA 2 , PGE 2 , PGD 2 , PGI 2 , and PGF 2␣ ). The physiological roles of PG are both diverse and complex, with effects on kidney ion transport, vascular homeostasis, gastrointestinal protection and motility, pregnancy and parturition, sleep, and immune function (1-3). In particular, the primary mediators of pain and inflammation are PGE 2 and PGI 2 (4), whereas pyresis is mediated by PGE 2 through the EP3 receptor (5).Two major cyclooxygenase isoforms are known, each with distinct roles. Expression patterns suggest that the constitutively expressed COX-1 plays housekeeping functions, whereas the inducible COX-2 is implicated in inflammatory processes. Exceptions to this paradigm have been uncovered with observations of constitutive COX-2 expression in several neuronal structures of the brain and in the kidney (6 -9). Thus, although COX-2 plays a pivotal role in inflammation, it also serves housekeeping functions. Indeed, the phenotype of the COX-2 null mice is indicative of COX-2 roles during kidney dev...