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

Abstract

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...

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

“…Because PGI 2 and PGE 2 have some redundant functions (8), this increase in PGI 2 generation might act as a compensatory mechanism to ameliorate the physiologic consequences of mPGES1 deficiency. Similar reductions in basal PGE 2 generation with shunting have been reported in other tissue preparations from mPges1 Ϫ/Ϫ mice (41,42). We also found prominent differences in renal prostanoid generation between male and female mice in our studies with basal levels of prostanoid excretion that are almost fourfold higher in female than male mice.…”

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

“…Thus, in the mPGES-1-deficient colon tissues, COX-2-derived prostaglandin H 2 is metabolically shunted into the PGD 2 /PGI 2 -synthetic pathway. In this regard, Boulet et al (2004) have also shown that mPGES-1 deficiency increased the production of PGs other than PGE 2 in the gastric mucosa.…”

Effects of AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide], a novel inhibitor of human microsomal prostaglandin E synthase-1, on prostanoid biosynthesis in human monocytes in vitro

“…However, Boulet et al [10] studied the shunting of PGH 2 to alternative prostanoid pathways in the presence of complete and incomplete loss of mPGES-1 gene and they did not detect a significant redirection towards TXB 2 in peritoneal macrophages under similar experimental conditions. The reason of these discrepant results is unclear.…”

“…However, in the stomachs of mice lacking mPGES-1 a shift from PGE 2 to all other prostanoids, i.e. TXA 2 , PGD 2 , PGF 2 , and 5 1 inhibition in the GI tract [10]. Further studies addressing this issue in appropriate animal models are required.…”