title: Vitamin D Receptor-Dependent Signaling Protects Mice From Dextran Sulfate Sodium-Induced Colitis.
abstract: Low vitamin D status potentiates experimental colitis, but the vitamin D-responsive cell in colitis has not been defined. We hypothesized that vitamin D has distinct roles in colonic epithelial cells and in nonepithelial cells during colitis. We tested this hypothesis by using mice with vitamin D receptor (VDR) deletion from colon epithelial cells (CEC-VDRKO) or nonintestinal epithelial cells (NEC-VDRKO). Eight-week-old mice were treated with 1.35% dextran sulfate sodium (DSS) for 5 days and then euthanized 2 or 10 days after removal of DSS. DSS induced body weight loss and increased disease activity index and spleen size. This response was increased in NEC-VDRKO mice but not CEC-VDRKO mice. DSS-induced colon epithelial damage and immune cell infiltration scores were increased in both mouse models. Although the epithelium healed between 2 and 10 days after DSS administration in control and CEC-VDRKO mice, epithelial damage remained high in NEC-VDRKO mice 10 days after removal of DSS, indicating delayed epithelial healing. Gene expression levels for the proinflammatory, M1 macrophage (Mɸ) cytokines tumor necrosis factor-α, nitric oxide synthase 2, and interleukin-1β were significantly elevated in the colon of NEC-VDRKO mice at day 10. In vitro experiments in murine peritoneal Mɸs demonstrated that 1,25 dihydroxyvitamin D directly inhibited M1 polarization, facilitated M2 polarization, and regulated Mɸ phenotype switching toward the M2 and away from the M1 phenotype. Our data revealed unique protective roles for vitamin D signaling during colitis in the colon epithelium as well as nonepithelial cells in the colon microenvironment (i.e., modulation of Mɸ biology).
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47906.
authors.forename: Fa
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47906.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Purdue University Interdisciplinary Life Sciences Ph.D. Training Program, Purdue University, West Lafayette, Indiana 47906.
authors.forename: Marsha L
authors.initials: ML
authors.lastname: DeSmet
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47906.|Center for Cancer Research, West Lafayette, Indiana 47907.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Snyder
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47906.
authors.forename: Keke C
authors.initials: KC
authors.lastname: Fairfax
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47906.|Center for Cancer Research, West Lafayette, Indiana 47907.
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection / Q000235:genetics*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018167:Receptors, Calcitriol; D016264:Dextran Sulfate