TGF-α reduces bradykinin-stimulated ion transport and prostaglandin release in human colonic epithelial cells

Abstract

The effect of chronic exposure to transforming growth factor-α (TGF-α) on bradykinin-stimulated acute prostanoid production and ion secretion in monolayers of HCA-7 colony 29 colonic epithelial cells has been studied. Monolayers synthesized prostaglandin E2(PGE2) at a basal rate of 2.10 ± 0.31 pg ⋅ monolayer−1 ⋅ min−1over 24 h. Bradykinin (10−8–10−5M) dose dependently increased acute PGE2 release by three orders of magnitude. This was associated with a rise in cAMP from 1.60 ± 0.14 to 2.90 ± 0.1 pmol/monolayer ( P < 0.02) and a dose-dependent increase in short-circuit current (SCC). When monolayers were primed by a 24-h exposure to TGF-α, basal PGE2 release rose to 6.31 ± 0.38 pg ⋅ monolayer−1 ⋅ min−1(TGF-α concn 10 ng/ml; P = 0.001). However, the stimulation of acute prostaglandin release, intracellular cAMP, and increased SCC by bradykinin was significantly reduced by preincubation with TGF-α. Priming with PGE2(10−8–10−6M) over 24 h mimicked the effect of TGF-α on bradykinin-induced changes in cAMP and SCC. These data suggest that enhanced chronic release of prostaglandins in response to stimulation with TGF-α may downregulate acute responses to bradykinin. In vivo, TGF-α could have an important modulatory function in regulating secretion under inflammatory conditions.