title: The role of PGE2 in intestinal inflammation and tumorigenesis.
abstract: Release of the free fatty acid arachidonic acid (AA) by cytoplasmic phospholipase A2 (cPLA2) and its subsequent metabolism by the cyclooxygenase and lipoxygenase enzymes produces a broad panel of eicosanoids including prostaglandins (PGs). This study sought to investigate the roles of these mediators in experimental models of inflammation and inflammation-associated intestinal tumorigenesis. Using the dextran sodium sulfate (DSS) model of experimental colitis, we first investigated how a global reduction in eicosanoid production would impact intestinal injury by utilizing cPLA2 knockout mice. cPLA2 deletion enhanced colonic injury, reflected by increased mucosal ulceration and pro-inflammatory cytokine expression. Increased disease severity was associated with a significant reduction in the levels of several eicosanoid metabolites, including PGE2. We further assessed the precise role of PGE2 synthesis on mucosal injury and repair by utilizing mice with a genetic deletion of microsomal PGE synthase-1 (mPGES-1), the terminal synthase in the formation of inducible PGE2. DSS exposure caused more extensive acute injury as well as impaired recovery in knockout mice compared to wild-type littermates. Increased intestinal damage was associated with both reduced PGE2 levels as well as altered levels of other eicosanoids including PGD2. To determine whether this metabolic redirection impacted inflammation-associated intestinal tumorigenesis, Apc(Min/+) and Apc(Min/+):mPGES-1(-/-) mice were exposed to DSS. DSS administration caused a reduction in the number of intestinal polyps only in Apc(Min/+):mPGES-1(-/-) mice. These results demonstrate the importance of the balance of prostaglandins produced in the intestinal tract for maintaining intestinal homeostasis and impacting tumor development.
authors.affiliation: Center for Molecular Medicine and Colon Cancer Prevention, University of Connecticut Health Center, Farmington, CT 06030, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Montrose
authors.affiliation: Center for Molecular Medicine and Colon Cancer Prevention, University of Connecticut Health Center, Farmington, CT 06030, United States.
authors.forename: Masako
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, United States.
authors.forename: Simona
authors.initials: S
authors.lastname: Zarini
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, United States.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: McAleer
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, United States.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Vella
authors.affiliation: Center for Molecular Medicine and Colon Cancer Prevention, University of Connecticut Health Center, Farmington, CT 06030, United States. Electronic address: rosenberg@uchc.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D003092:Colitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071876:Prostaglandin-E Synthases
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D054513:Group IV Phospholipases A2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: Colitis; Cytosolic phosphlipase A(2); Intestine; Microsomal prostaglandin E synthase-1; Prostaglandins; Tumorigenesis