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Articles in PresS, published online ahead of print August 14, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00414.2001
Submitted on August 24, 2001
Accepted on August 1, 2002
1 Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
* To whom correspondence should be addressed. E-mail: mckayd{at}mcmaster.ca.
Growth factors have been shown to affect a variety of epithelial functions. Here we examined the ability of transforming growth factor ß (TGFß) to modulate epithelial ion transport and permeability. Filter-grown monolayers of human colonic epithelia, T84 and HT-29 cells, were treated with TGFß (0.1-100 ng/ml, 15min-72h), or infected with an adenoviral vector encoding TGFß (Ad-TGFß) for 144h. Ion transport (i.e. short-circuit current, Isc) and transepithelial resistance (TER) were assessed in Ussing chambers. Neither recombinant TGFß nor Ad-TGFß infection affected baseline Isc, however exposure to 
1 ng/ml TGFß led to a significant (30-50%) reduction in the Isc responses to forskolin, vasoactive intestinal peptide and cholera toxin (agents that evoke chloride secretion via cAMP mobilization) and the cell permeant dibutyryl cAMP. Pharmacological analysis of signaling pathways revealed that the inhibition of cAMP-driven epithelial chloride secretion by TGFß was blocked by pre-treatment with SB203580, a specific inhibitor of p38 MAP kinase, but not by inhibitors of JNK, ERK 1/2 MAP kinase, or phosphatidylinositol-3' kinase. TGFß enhanced the barrier function of the treated monolayers by up to 3-fold as assessed by TER; however this event was temporally displaced from the altered Isc response, being statistically significant only at 72h post-treatment. Thus, in addition to TGFß 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.
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