Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: Interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro

Recombinant growth factors and proinflammatory cytokines were added to primary cultures of human intrahepatic biliary duct epithelia to test for their ability to stimulate DNA synthesis and elicit cytokine production. Interleukin-6 and hepatocyte and epidermal growth factors were found to increase the DNA labeling index of biliary duct epithelium from fourfold to sixfold 24 hr after their addition to primary biliary duct epithelium cultures maintained in serum-free medium. The proliferative responses to all three biliary duct epithelium mitogens peaked within 24 hr, and hepatocyte growth factor was effective over a concentration range of 1.0 to 50 ng/ml, whereas interleukin-6 was effective from 1 to 1,000 U/ml. Insulin-like growth factor, phorbol myristate acetate, interleukin-1 beta and platelet-derived growth factor BB showed mild stimulatory effects, whereas interleukin-4, gamma-interferon, phytohemagglutinin and platelet-derived growth factors AA and AB did not increase DNA synthesis in biliary duct epithelium. Interleukin-1 beta and phorbol myristate acetate were also shown to induce in a dose-dependent fashion a threefold to fivefold increase of interleukin-6 production as measured by enzyme-linked immunosorbent assay in human primary biliary duct epithelium cultures, when compared with hepatocyte growth factor, epidermal growth factor, insulin-like growth factor, phytohemagglutinin, tumor necrosis factor-alpha or platelet-derived growth factor. These results show that interleukin-6 participates in growth regulation of human biliary duct epithelium. This could be exerted in a paracrine or autocrine manner.(ABSTRACT TRUNCATED AT 250 WORDS)