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Am J Physiol Cell Physiol 283: C1667-C1674, 2002. First published August 14, 2002; doi:10.1152/ajpcell.00414.2001
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Vol. 283, Issue 6, C1667-C1674, December 2002

TGF-beta effects on epithelial ion transport and barrier: reduced Clminus secretion blocked by a p38 MAPK inhibitor

Kathryn Howe1, Jack Gauldie2, and Derek M. McKay1

1 Intestinal Disease Research Program and 2 Center for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Growth factors affect a variety of epithelial functions. We examined the ability of TGF-beta to modulate epithelial ion transport and permeability. Filter-grown monolayers of human colonic epithelia, T84 and HT-29 cells, were treated with TGF-beta (0.1-100 ng/ml, 15 min-72 h) or infected with an adenoviral vector encoding TGF-beta (Ad-TGFbeta ) for 144 h. Ion transport (i.e., short-circuit current, Isc) and transepithelial resistance (TER) were assessed in Ussing chambers. Neither recombinant TGF-beta nor Ad-TGFbeta infection affected baseline Isc; however, exposure to >= 1 ng/ml TGF-beta led to a significant (30-50%) reduction in the Isc responses to forskolin, vasoactive intestinal peptide, and cholera toxin (agents that evoke Cl- secretion via cAMP mobilization) and to the cell-permeant dibutyryl cAMP. Pharmacological analysis of signaling pathways revealed that the inhibition of cAMP-driven epithelial Cl- secretion by TGF-beta was blocked by pretreatment with SB-203580, a specific inhibitor of p38 MAPK, but not by inhibitors of JNK, ERK1/2 MAPK, or phosphatidylinositol 3'-kinase. TGF-beta enhanced the barrier function of the treated monolayers by up to threefold as assessed by TER; however, this event was temporally displaced from the altered Isc response, being statistically significant only at 72 h posttreatment. Thus, in addition to TGF-beta promotion of epithelial barrier function, we show that this growth factor also reduces responsiveness to cAMP-dependent secretagogues in a chronic manner and speculate that this serves as a braking mechanism to limit secretory enteropathies.

short-circuit current; T84 epithelia; growth factor; transepithelial resistance


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