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 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. 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. Prostaglandins (PG) 1The abbreviations used are: PG, prostaglandin; COX, cyclooxygenase; EIA, enzyme immunoassay; FBS, fetal bovine serum; mPGES, microsomal prostaglandin E synthase; LC-MS, liquid chromatography-mass spectroscopy; LPS, lipopolysaccharide; PBS, phosphate buffered saline; TX, thromboxane; ANOVA, analysis of variance.1The abbreviations used are: PG, prostaglandin; COX, cyclooxygenase; EIA, enzyme immunoassay; FBS, fetal bovine serum; mPGES, microsomal prostaglandin E synthase; LC-MS, liquid chromatography-mass spectroscopy; LPS, lipopolysaccharide; PBS, phosphate buffered saline; TX, thromboxane; ANOVA, analysis of variance. 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 PGH2 serves as common precursor to all five major prostanoids (TXA2, PGE2, PGD2, PGI2, and PGF2α). 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 (1Sugimoto Y. Narumiya S. Ichikawa A. Prog. Lipid Res. 2000; 39: 289-314Crossref PubMed Scopus (167) Google Scholar, 2Funk C.D. Science. 2001; 294: 1871-1875Crossref PubMed Scopus (3029) Google Scholar, 3Narumiya S. FitzGerald G.A. J. Clin. Invest. 2001; 108: 25-30Crossref PubMed Scopus (466) Google Scholar). In particular, the primary mediators of pain and inflammation are PGE2 and PGI2 (4Murata T. Ushikubi F. Matsuoka T. Hirata M. Yamasaki A. Sugimoto Y. Ichikawa A. Aze Y. Tanaka T. Yoshida N. Ueno A. Oh-ishi S. Narumiya S. Nature. 1997; 388: 678-682Crossref PubMed Scopus (680) Google Scholar), whereas pyresis is mediated by PGE2 through the EP3 receptor (5Ushikubi F. Segi E. Sugimoto Y. Murata T. Matsuoka T. Kobayashi T. Hizaki H. Tuboi K. Katsuyama M. Ichikawa A. 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A. 2003; PubMed Scopus Google Scholar). mPGES-1 plays an important role during inflammation in the other mPGES-1 to PGE2 production is and the of mPGES-1 activity on the production of other prostaglandins been we by the impact of mPGES-1 deficiency on synthesis of major prostaglandins and both in cultured macrophages and in that mPGES-1 is for PGE2 in a in and peritoneal In vivo, we that mPGES-1 is for PGE2 is several of and in significantly to PGE2 levels in kidney, and The stomachs of mPGES-1-null mice exhibited alterations for all changes in mRNA expression of other terminal synthases. data an of mPGES-1 to basal, PGE2 and an in other in the stomach of mice for mPGES-1 Prostaglandins and were were as and a and COX-2 were expressed in cells and as M. A. J.A. Riendeau D. M.D. 2002; PubMed Scopus Google Scholar, M. M.D. Biochem. J. 1995; PubMed Scopus (133) Google Scholar, M.D. M. J.A. Arch. Biochem. Biophys. 1994; PubMed Scopus Google Scholar). mice were S. Akira and have been S. Matsumoto M. Takeda K. Akira S. J. Immunol. 2002; 168: 5811-5816Crossref PubMed Scopus (272) Google Scholar). of the mPGES-1 by mPGES-1 a mPGES-1 protein with wild but a acid and were at and in a with to and were at in to and were were with of LPS or and were were in liquid and at and were in and the were for and prostaglandin Both and both were each with one for prostaglandin and microsomal protein and the other for each for mPGES-1 wild type, heterozygote, and null mice were used as macrophage source and to for by their were with of with with were to Resident macrophages were by peritoneal of were and in with and mice were in in at a of cells and to at with cells were by were with with and or LPS at for the the and for PGE2, PGF2α, and by to the by were by also of peritoneal cells were in at a of and as macrophages were with and with of with the of were on and by were at in with of and with a and for The were first at for and the used for protein and for PG of the used to by at for The in with a by the as were at and and macrophage were by in and to with COX-2, and mPGES-1 protein and of that were on each for The were mPGES-1 and in with and The and and were used at a of by and analysis were a and Prostaglandins PGF2α, PGD2, and were by liquid were by the of prostaglandins as PGE2 as for both PGE2 and were and and the to a were a a and Prostaglandins were at a to acid of prostaglandins a ion with the The source at and and were and prostaglandin for and to the were in of and at for were with of at for and at for The to a an of and at for at for The with in and of each were on by to the and an the with of of reaction reaction to for of at least different in in the absence of were to for and reaction were and for and The of the and used are shown in The and for the of a with a at the and a at the The a at the and a at the for all by on an in a of of of and and for the in a that of the and The of of removal at at of at for and at for reaction a reaction in used of to as a for and as in of the the and used for in a analysis of used to that of and were were at the of of mPGES-1 on PGE2 by of PGE2 by LPS-stimulated peritoneal macrophages shown to on the expression of mPGES-1 S. Matsumoto M. Takeda K. Akira S. J. Immunol. 2002; 168: 5811-5816Crossref PubMed Scopus (272) Google Scholar). macrophages vary widely in their and we mPGES-1 an role in a different macrophage that we PGE2 in the of and peritoneal macrophages mPGES-1 and mice and COX-2 and mPGES-1 expression in each of in the absence or of LPS stimulation. As LPS-stimulated peritoneal macrophages PGE2 in that by PGE2 by LPS to significantly PGE2 by mPGES-1-/- the of PGE2 by cells that of wild cells macrophages levels of PGE2 with to with peritoneal LPS resulted in a in PGE2 a and macrophages PGE2 of one mPGES-1 to a 50% reduction in PGE2 whereas absence PGE2 by this LPS of mPGES-1-/- macrophages resulted in a in PGE2 with mPGES-1-/- cells Thus, a of PGE2 in the absence of mPGES-1 for an important and role for mPGES-1 in PGE2 synthesis by macrophages and a of LPS-stimulated PGE2 production of mPGES-1 in mPGES-1 and COX-2 Expression Both of the mPGES-1 on PGE2 we mPGES-1 and COX-2 protein by in and macrophages wild type, and mPGES-1-null mice. both macrophage types wild and mice expressed levels of mPGES-1 LPS for mPGES-1 protein with levels in cells of found in wild cells and COX-2 protein expression induced by LPS and not significantly different in wild and COX-2 expression in and mPGES-1-/- macrophages to the levels induced in wild cells and for mPGES-1 and COX-2 were with of LPS not The of mPGES-1 and COX-2 several LPS-stimulated wild and macrophages expressed of mPGES-1 protein macrophages PGE2, with a COX-2 protein Both macrophage types showed a 50% decrease of PGE2 the mPGES-1 protein by in cells These suggest that COX-2 and mPGES-1 PGE2 with COX-2 for the in PGE2 and and mPGES-1 in LPS-stimulated cells in a in the of of COX-2 in the absence of mPGES-1 to an PGH2 for prostanoid this by the production of other prostaglandins PGF2α, PGD2, and the by and macrophages of all three in in mPGES-1-/- macrophages with wild Both and macrophages showed for that did not macrophages mPGES-1 wild cells Thus, the absence of mPGES-1 the PG of both macrophage but in a different mPGES-1 for PGE2 in the absence of mPGES-1 the production of prostanoids in mice. PGE2 and other prostaglandins were in of mice that been with LPS or a PGE2 in kidney, and of wild to In LPS resulted in a decrease of gastric PGE2 levels PGE2 induced by LPS in mPGES-1-/- mice the PGE2 in several of mPGES-1 mice were in wild a with wild mice not that mPGES-1 is for LPS-inducible PGE2 production in kidney, and during and stomachs of mPGES-1-/- mice PGE2 and whereas stomach PGF2α, and were significantly and mPGES-1-/- mice exhibited a of and a for a of not of the other or showed changes in prostaglandins other PGE2 in the absence of mPGES-1. that deletion of mPGES-1 LPS-stimulated PGE2 production in vivo and tissue-specific alterations of prostanoid in stomach and kidney. mPGES-1 in expression of COX-2, and COX-1 in of and mice by in are of the used in each of mPGES-1 protein were expressed in spleen, kidney, and stomach of wild mice but not in brain or in of mPGES-1-null mice. mPGES-1 protein induced by LPS in brain and of wild mice. COX-1 protein of or COX-2 expression in brain and of all with to LPS induced a of COX-2 protein expression in spleen, and kidney. The COX-2 protein levels in stomach were the of data not and were significantly COX-1 mPGES-1 to PGE2 in constitutive expression of mPGES-1 protein in several and PGE2 levels in and a of mPGES-1 to PGE2 this by the prostanoid in of wild type, and mPGES-1-null mice. PGE2 in mPGES-1-/- with wild in brain kidney and stomach changes were in and not and showed a decrease in their PGE2 levels to wild but the reduction not Other prostaglandins were also The absence of a mPGES-1 to a in and in stomach mPGES-1-/- exhibited a in and in not that mPGES-1 to 50% of PGE2 in kidney, and 80-90% in stomach and spleen, The prostaglandin of the stomach by the lack of mPGES-1 in the of in in PGD2, and in stomachs of mPGES-1-/- mice an in terminal PG expression or shunting of PGH2 terminal PG synthases. the expression levels of and COX-2 were by in wild and wild and mPGES-1-null and used for each are in for kidney and stomach are shown in As LPS an of the mPGES-1 and COX-2 in of wild mice and The of COX-2 protein by with mRNA by in mice not in the kidney expression of other terminal synthases wild and mPGES-1-null were in that LPS a decrease in levels of in the mPGES-1-/- showed a in COX-2 to wild type, this not that absence of mPGES-1 not in an of the expression of terminal PG synthases. The gastric PG in mPGES-1 null mice may a of a in stomach COX-2 expression and PGH2 shunting to other terminal PG synthases. we the impact of or mPGES-1 activity on prostaglandin by macrophage types in and by and in major can be we showed that mPGES-1 is in for PGE2 by and peritoneal in a In we uncovered a of PGE2 activity in peritoneal we the of mPGES-1 for PGE2 in several of mice and showed for the first time a of mPGES-1 activity to PGE2 production in we found that the prostaglandin of cells and is not by the absence of mPGES-1 activity in the a of all other prostanoids may an in PGH2 to other terminal synthases. in on each of PGE2 by and peritoneal macrophages on mPGES-1 activity to produce PGE2 peritoneal macrophages exhibited PGE2 activity with PGH2 can to PGE2 and with a of E. Res. Google Scholar), it the PGE2 by mPGES-1-/- macrophages or the of PGH2 to PGE2. in the of mPGES-1-/- and we the that PGE2 in through the recently The of PGE2 by and peritoneal with of mPGES-1 and COX-2, important on the of in PGE2 The PGE2 synthesis of peritoneal macrophages been and to COX-2 expression and arachidonic activity in cells S. Kobayashi T. H. J. Lipid Mediat. 1994; Google Scholar, S. Kobayashi T. H. Prostaglandins Other Lipid Mediat. 1998; PubMed Scopus Google Scholar). we have not arachidonic we found that a COX-2 in macrophages by PGE2 synthesis and that a reduction in mPGES-1 protein in cells by a reduction in PGE2 that the of PGE2 synthesis in LPS-stimulated macrophages is by both COX-2 and mPGES-1 protein of mPGES-1 in synthesis in LPS-stimulated macrophages is on mPGES-1 S. Matsumoto M. Takeda K. Akira S. J. Immunol. 2002; 168: 5811-5816Crossref PubMed Scopus (272) Google Scholar, K. J.M. Saha S. D. J.E. Jakobsson P.J. T.J. Proc. Natl. Acad. Sci. U. S. 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