title: Tgf-beta downregulation of distinct chloride channels in cystic fibrosis-affected epithelia.
abstract: BACKGROUND
  The cystic fibrosis transmembrane conductance regulator (CFTR) and Calcium-activated Chloride Conductance (CaCC) each play critical roles in maintaining normal hydration of epithelial surfaces including the airways and colon. TGF-beta is a genetic modifier of cystic fibrosis (CF), but how it influences the CF phenotype is not understood.
  
  
  OBJECTIVE
  We tested the hypothesis that TGF-beta potently downregulates chloride-channel function and expression in two CF-affected epithelia (T84 colonocytes and primary human airway epithelia) compared with proteins known to be regulated by TGF-beta.
  
  
  RESULTS
  TGF-beta reduced CaCC and CFTR-dependent chloride currents in both epithelia accompanied by reduced levels of TMEM16A and CFTR protein and transcripts. TGF-beta treatment disrupted normal regulation of airway-surface liquid volume in polarized primary human airway epithelia, and reversed F508del CFTR correction produced by VX-809. TGF-beta effects on the expression and activity of TMEM16A, wtCFTR and corrected F508del CFTR were seen at 10-fold lower concentrations relative to TGF-beta effects on e-cadherin (epithelial marker) and vimentin (mesenchymal marker) expression. TGF-beta downregulation of TMEM16A and CFTR expression were partially reversed by Smad3 and p38 MAPK inhibition, respectively.
  
  
  CONCLUSIONS
  TGF-beta is sufficient to downregulate two critical chloride transporters in two CF-affected tissues that precedes expression changes of two distinct TGF-beta regulated proteins. Our results provide a plausible mechanism for CF-disease modification by TGF-beta through effects on CaCC.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: William T
authors.initials: WT
authors.lastname: Harris
authors.affiliation: University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kortyka
authors.affiliation: Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Kotha
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Ostmann
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Amir
authors.initials: A
authors.lastname: Rezayat
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Anusha
authors.initials: A
authors.lastname: Sridharan
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sanders
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; Department of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; Department of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Clancy
mesh_terms: D000075369:Anoctamin-1; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; C505032:CFTR protein, human; C492109:CLCA1 protein, human; D018118:Chloride Channels; D002712:Chlorides; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP