title: Crucial role of macrophage selenoproteins in experimental colitis.
abstract: Inflammation is a hallmark of inflammatory bowel disease (IBD) that involves macrophages. Given the inverse link between selenium (Se) status and IBD-induced inflammation, our objective was to demonstrate that selenoproteins in macrophages were essential to suppress proinflammatory mediators, in part, by the modulation of arachidonic acid metabolism. Acute colitis was induced using 4% dextran sodium sulfate in wild-type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate (0.08 ppm; sodium selenite), and two supraphysiological levels in the form of Se-supplemented (0.4 ppm; sodium selenite) and high Se (1.0 ppm; sodium selenite) diets. Selenocysteinyl transfer RNA knockout mice (Trsp(fl/fl)LysM(Cre)) were used to examine the role of selenoproteins in macrophages on disease progression and severity using histopathological evaluation, expression of proinflammatory and anti-inflammatory genes, and modulation of PG metabolites in urine and plasma. Whereas Se-deficient and Se-adequate mice showed increased colitis and exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival of mice and decreased colitis-associated inflammation with an upregulation of expression of proinflammatory and anti-inflammatory genes. Metabolomic profiling of urine suggested increased oxidation of PGE2 at supraphysiological levels of Se that also correlated well with Se-dependent upregulation of 15-hydroxy-PG dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of 15-PGDH, lack of selenoprotein expression in macrophages, and depletion of infiltrating macrophages indicated that macrophage-specific selenoproteins and upregulation of 15-PGDH expression were key for Se-dependent anti-inflammatory and proresolving effects. Selenoproteins in macrophages protect mice from dextran sodium sulfate-colitis by enhancing 15-PGDH-dependent oxidation of PGE2 to alleviate inflammation, suggesting a therapeutic role for Se in IBD.
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
authors.forename: Naveen
authors.initials: N
authors.lastname: Kaushal
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
authors.forename: Avinash K
authors.initials: AK
authors.lastname: Kudva
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
authors.forename: Christopher
authors.initials: C
authors.lastname: Chiaro
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033; and.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033; and.
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.affiliation: Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802;
authors.forename: Margherita T
authors.initials: MT
authors.lastname: Cantorna
authors.affiliation: Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802; ksprabhu@psu.edu.
authors.forename: K Sandeep
authors.initials: KS
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D019587:Dietary Supplements; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics / Q000276:immunology; D012643:Selenium / Q000494:pharmacology; D051140:Selenoproteins / Q000235:genetics / Q000276:immunology*
chemical_list: D012346:RNA, Transfer, Amino Acyl; D051140:Selenoproteins; C112705:selenocysteinyl-tRNA; D016264:Dextran Sulfate; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D012643:Selenium; D015232:Dinoprostone