TGFbeta down-regulation of the CFTR: a means to limit epithelial chloride secretion

Exp Cell Res. 2004 Aug 15;298(2):473-84. doi: 10.1016/j.yexcr.2004.04.026.


Transforming growth factor beta (TGFbeta) is a multifunctional cytokine with effects on many cell types. We recently showed that in addition to epithelial barrier enhancing properties, TGFbeta causes diminished cAMP-driven chloride secretion in colonic epithelia, in a manner that is p38 MAPK-dependent. In this study, we sought to further delineate the mechanism behind TGFbeta diminution of chloride secretion. Using colonic and kidney epithelial cell lines, we found that exposure to TGFbeta causes dramatic changes in the expression and localization of the apical membrane chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR). In TGFbeta-treated colonic epithelia (T84 and HT-29), CFTR mRNA was significantly reduced 2-24 h post-cytokine exposure. At a time consistent with decreased colonic epithelial secretory responses (16 h), TGFbeta treatment caused diminished intracellular CFTR protein expression (confocal microscopy) and reduced channel expression in the apical membrane during stimulated chloride secretion (biotinylation assay). In comparison, polarized kidney epithelia (MDCK) treated with TGFbeta displayed similarly reduced secretory responses to cAMP stimulating agents; however, a perinuclear accumulation of CFTR was observed, contrasting the diffuse cytoplasmic CFTR expression of control cells. Our data indicate that TGFbeta has profound effects on the expression and subcellular localization of an important channel involved in cAMP-driven chloride secretion, and thus suggest TGFbeta represents a key regulator of fluid movement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Cell Membrane Permeability / drug effects
  • Cell Membrane Permeability / physiology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Chlorides / metabolism*
  • Cyclic AMP / agonists
  • Cyclic AMP / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Cytoskeleton / ultrastructure
  • Dogs
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Humans
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Water-Electrolyte Balance / drug effects
  • Water-Electrolyte Balance / physiology


  • CFTR protein, human
  • Chlorides
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cyclic AMP