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    TGF-β1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis


    Nguyen, N. and Fernando, S.T. and Biette, K.A. and Hammer, J.A. and Capocelli, K.E. and Kitzenberg, D.A. and Glover, L.E. and Colgan, S.P. and Furuta, G.T. and Masterson, Joanne C. (2017) TGF-β1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis. Mucosal immunology, 11. pp. 415-426. ISSN 1935-3456

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    Abstract

    Barrier dysfunction has been implicated in the pathophysiology of eosinophilic esophagitis (EoE). TGF-β1, a potent pleiotropic molecule, is increased in EoE, however, no study has evaluated its influence on esophageal epithelial barrier. We hypothesized that TGF-β1 regulates barrier dysfunction in EoE. We aimed to determine the role of TGF-β1 in epithelial barrier in models of EoE. To examine the impact of TGF-β1 on esophageal barrier, immortalized human esophageal epithelial (EPC2-hTERT) cells were exposed to TGF-β1 during the 3-dimensional air liquid interface (3D-ALI) model in vitro. TGF-β1 exposure diminished EPC2-hTERT barrier function as measured by transepithelial electrical resistance (TEER) and 3kDa FITC dextran paracellular flux (FITC Flux) and H&E assessment revealed prominent cellular separation. In analysis of epithelial barrier molecules, TGF-β1 led to the specific reduction in expression of the tight-junction molecule, claudin-7 and this was prevented by TGF-β receptor I inhibitor. shRNA mediated claudin-7 knockdown diminished epithelial barrier function, while claudin-7 overexpression resulted in protection from TGF-β1-mediated barrier dysfunction. In analysis of pediatric EoE biopsies claudin-7 expression was decreased, altered localization was observed by immunofluorescence analysis and the TGF-β1 downstream transcription factor phosphorylated SMAD2/3 (pSMAD2/3) was increased. Our data suggest that TGF-β1 participates in esophageal epithelial barrier dysfunction through claudin-7 dysregulation.

    Item Type: Article
    Additional Information: This is the postprint version of the published article. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
    Keywords: Eosinophilic Esophagitis; Tight Junctions; Claudin-7; pSMAD2/3; Epithelial Barrier;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 10938
    Identification Number: https://doi.org/10.1038/mi.2017.72
    Depositing User: Joanne Masterson
    Date Deposited: 15 Jul 2019 16:09
    Journal or Publication Title: Mucosal immunology
    Publisher: Springer Nature
    Refereed: Yes
    URI:

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