TGF-alpha reduces bradykinin-stimulated ion transport and prostaglandin release in human colonic epithelial cells.
The effect of chronic exposure to transforming growth factor-alpha (TGF-alpha) 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-1 over 24 h. Bradykinin (10(-8)-10(-5) M) 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-alpha, basal PGE2 release rose to 6.31 +/- 0.38 pg. monolayer-1. min-1 (TGF-alpha 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-alpha. Priming with PGE2 (10(-8)-10(-6) M) over 24 h mimicked the effect of TGF-alpha on bradykinin-induced changes in cAMP and SCC. These data suggest that enhanced chronic release of prostaglandins in response to stimulation with TGF-alpha may downregulate acute responses to bradykinin. In vivo, TGF-alpha could have an important modulatory function in regulating secretion under inflammatory conditions.
Beltinger
J
J
Division of Gastroenterology, University Hospital, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
Hawkey
C J
CJ
Stack
W A
WA
D016718:Arachidonic Acid / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D003106:Colon; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology* / Q000502:physiology
D002712:Chlorides; D007527:Isoenzymes; D008565:Membrane Proteins; D016211:Transforming Growth Factor alpha; D005576:Colforsin; D016718:Arachidonic Acid; D002217:Carbachol; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001920:Bradykinin