title: MicroRNA-346 mediates tumor necrosis factor α-induced downregulation of gut epithelial vitamin D receptor in inflammatory bowel diseases.
abstract: BACKGROUND
  We recently reported that the gut epithelial vitamin D receptor (VDR) signaling inhibits colitis through inhibition of intestinal epithelial cell apoptosis, and the level of colonic epithelial VDR is markedly reduced in patients with inflammatory bowel diseases (IBD). VDR downregulation promotes colitis, but the mechanism underlying VDR downregulation in IBD is unknown.
  
  
  METHODS
  VDR expression was analyzed in colon cancer cells under proinflammatory cytokine treatment. VDR as a target of miR-346 was confirmed using colon cancer cell culture. The relationship among inflammation, miR-346, and VDR was assessed in human IBD biopsies and experimental colitis models.
  
  
  RESULTS
  We showed that tumor necrosis factor α (TNF-α) suppresses VDR expression while simultaneously upregulating miR-346 in human colon cancer cells. Further studies demonstrated that miR-346 inhibits VDR by a specific target sequence in the 3' untranslated region of the human VDR transcript, and blockade of miR-346 with a hairpin inhibitor abrogates the ability of TNF-α to inhibit VDR, confirming that TNF-α downregulates VDR by inducing miR-346. Consistently, in human IBD biopsies, the reduction of epithelial VDR is associated with increased immune cell infiltration and elevation of TNF-α and miR-346. In an experimental model of colitis, mucosal VDR expression is reduced over time with the progression of colitis, inversely correlated with the induction of TNF-α and miR-346 in the mucosa.
  
  
  CONCLUSIONS
  These data suggest that during mucosal inflammation TNF-α induces miR-346, which downregulates epithelial VDR. Mucosal VDR reduction in turn compromises the integrity of the mucosal epithelial barrier, further driving mucosal inflammation and colitis development.
authors.affiliation: *Laboratory of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, Liaoning, China; †Division of Biological Sciences, Department of Medicine, The University of Chicago, Chicago, Illinois; and ‡Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China. Dr Chen is now with the Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, China.
authors.forename: Yunzi
authors.initials: Y
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tianjing
authors.initials: T
authors.lastname: Liu
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Shi
authors.forename: Xin
authors.initials: X
authors.lastname: Ge
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C560923:MIRN346 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate