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PLoS One. 2014 Sep 30;9(9):e106842. doi: 10.1371/journal.pone.0106842. eCollection 2014.

Tgf-beta downregulation of distinct chloride channels in cystic fibrosis-affected epithelia.

Author information

1
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
2
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
3
University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
4
Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
5
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
6
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.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

PMID:
25268501
PMCID:
PMC4182049
DOI:
10.1371/journal.pone.0106842
[Indexed for MEDLINE]
Free PMC Article

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