ENDOTHELIN-1 SECRETION BY HUMAN GALLBLADDER EPITHELIAL-CELLS IN PRIMARY CULTURE

BACKGROUND: The three isoforms of endothelin (ET), ET-1, ET-2, and ET- 3 are potent contractile agonists for smooth muscle in a wide variety of tissues including the gallbladder. There is increasing evidence tha t endothelin acts in a paracrine fashion, however its cell source in t he gallbladder is unclear. EXPERIMENTAL DESIGN: To examine the product ion of ET by gallbladder and bile duct epithelium. RESULTS: We show th at human gallbladder epithelial cells in primary culture secrete endot helin. ET release was time-dependent, and intracellular ET was negligi ble, indicating de novo synthesis. Secretion was increased by physiolo gic concentrations of cholecystokinin. Epithelial cells lining hepatic cysts in primary culture also released ET, suggesting that the intrah epatic, as well as the extrahepatic biliary epithelium is a source of this cytokine. High performance liquid chromatography separation of th e conditioned medium from both cell types showed a single peak corresp onding to that of ET-1. In vivo, ET-1 was present in hepatic cyst flui d, but was not detectable in gallbladder or choledochal bile. On tissu e sections, both intrahepatic and extrahepatic bile duct epithelial ce lls were labeled with an anti-''big'' ET-1 polyclonal antibody. CONCLU SIONS: These results suggest that ET-1 is locally produced in the bili ary tract and by a paracrine route, could play a role in choledochal m otility and gallbladder contraction.