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

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Transforming growth factor β (TGFβ) is a multifunctional cytokine with effects on many cell types. We recently showed that in addition to epithelial barrier enhancing properties, TGFβ 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 TGFβ diminution of chloride secretion. Using colonic and kidney epithelial cell lines, we found that exposure to TGFβ causes dramatic changes in the expression and localization of the apical membrane chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR). In TGFβ-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), TGFβ 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 TGFβ 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 TGFβ has profound effects on the expression and subcellular localization of an important channel involved in cAMP-driven chloride secretion, and thus suggest TGFβ represents a key regulator of fluid movement.