title: Syndecan-1 Acts in Synergy with Tight Junction Through Stat3 Signaling to Maintain Intestinal Mucosal Barrier and Prevent Bacterial Translocation.
abstract: BACKGROUND
  Intestinal epithelial tight junction (TJ) is the principal determinant of mucosal permeability, defects of which have been correlated to inflammatory bowel disease. In this study, we investigated whether syndecan-1 (Sdc1), the predominant cell surface heparan sulfate proteoglycan, affects TJ proteins to protect intestinal barrier function.
  
  
  METHODS
  The role of Sdc1 in barrier function was examined in cultured colonic epithelial cells and dextran sodium sulfate-induced colitis mouse model. Barrier function was determined by transepithelial electrical resistance, bacterial translocation, and FITC-dextran flux. Canonical TJ proteins ZO-1 and occludin were measured by Western blot and immunofluoresence. Role of the Stat3 pathway was detected by Western blot and chromatin immunoprecipitation.
  
  
  RESULTS
  Overexpressed Sdc1 in Caco-2 cells attenuated transepithelial electrical resistance reduction, prevented bacterial translocation, and repressed FITC-dextran flux, whereas Sdc1 knockdown in HT29 cells resulted in a greater loss of barrier function. Supplementation of exogenous Sdc1 in colitis mice ameliorated the activity of colitis and barrier defect. Mechanistically, Sdc1 significantly modulated expressions of ZO-1 and occludin by activating Stat3, which directly bound to the promoter regions of ZO-1 and occludin. Furthermore, ZO-1 and occludin were found to bind to each other, and their repression could induce Sdc1 upregulation.
  
  
  CONCLUSIONS
  Sdc1 plays an important role in protecting the intestinal barrier function and preventing bacterial translocation, in synergy with TJ through Stat3 signaling in an Sdc1/Stat3/ZO-1 and occludin feedback loop. Sdc1 participates in the mechanism that is related to intestinal barrier function and colitis and represents a therapeutic target for novel anti-inflammatory bowel disease strategies.
authors.affiliation: *Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; †Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and ‡Department of Gastroenterology, Liuzhou Worker's Hospital, Liuzhou, China.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Wang
authors.forename: Runhua
authors.initials: R
authors.lastname: Li
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Tan
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001419:Bacteria / Q000254:growth & development; D001422:Bacterial Adhesion; D018988:Bacterial Translocation; D015153:Blotting, Western; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D053668:Syndecan-1; D016264:Dextran Sulfate