GAMMA-INTERFERON INHIBITS SECRETIN-INDUCED CHOLERESIS AND CHOLANGIOCYTE PROLIFERATION IN A MURINE MODEL OF CIRRHOSIS

Background/Aims: Cholangiocyte proliferation is associated with increa sed secretin receptor gene expression and secretin-induced choleresis. Since gamma-interferon has antiproliferative effects, we tested the h ypothesis that gamma-interferon inhibits ductal proliferation and secr etin-stimulated choleresis associated with cirrhosis. Methods: Mice we re treated with 0.1 ml of 25% carbon tetrachloride intraperitoneally t wice weekly and 5% alcohol in drinking mater for 12 weeks to induce ci rrhosis and subsequently gamma-interferon 10(5) intramuscularly was ad ministered daily for 10 weeks. We measured the effects of carbon tetra chloride and gamma-interferon on liver collagen content by morphometri c analysis and hydroxyproline content. We measured the effects of gamm a-interferon on ductal mass by morphometry and on ductal secretion by assessment of secretin receptor gene expression and secretin-induced c holeresis. Results: Compared to controls, there was an increase in liv er hydroxyproline content of carbon tetrachloride-treated mice with hi stologic evidence of cirrhosis. Gamma-interferon treatment significant ly decreased collagen liver content with loss of histologic features o f cirrhosis. Morphometry revealed an increased number of bile ducts in cirrhotic mice as compared to controls or cirrhotics who received gam ma-interferon. Secretin receptor mRNA levels were higher in cirrhotic mice compared to controls but this increase was inhibited by gamma-int erferon. Secretin stimulated ductal secretion in cirrhotic mice but no t control or cirrhotic mice who received gamma-interferon. Conclusions : We have established a murine model for cirrhosis and have shown, con sistent with our hypothesis, that gamma-interferon decreases collagen content, ductal mass and secretin-induced choleresis in cirrhotic mice .