EFFECT OF CHOLESTASIS AND BILE-ACIDS ON INTERFERON-INDUCED 2',5'-ADENYLATE SYNTHETASE AND NK CELL ACTIVITIES

Background/Aims: The mechanisms involved in resistance to interferon a lfa in patients with chronic hepatitis C are unclear. Both cirrhosis a nd cholestasis have been shown to be predictive of resistance. The aim of this study was to evaluate the influence of cholestasis and bile a cids on 2',5'-oligoadenylate synthetase and natural killer activities, which are both involved in the antiviral activity of interferon. Meth ods: 2',5'-Oligoadenylate synthetase activity was evaluated in spleen, liver, and isolated hepatocytes from bile duct-ligated rats, and the effect of bile acids in vitro on interferon-induced 2',5'-oligoadenyla te synthetase and natural killer activities was examined in fresh mono nuclear cells from healthy subjects. Results: Cholestasis had a time-d ependent inhibitory effect on 2',5'-oligoadenylate synthetase activity in liver, spleen, and isolated hepatocytes from cholestatic vats (-70 %, 86%, and 70% relative to baseline, respectively). In vitro, endogen ous bile acids had a concentration-dependent inhibitory effect on inte rferon-induced 2',5'-oligoadenylate synthetase and natural killer acti vities, which was related to their structure. This inhibitory effect c orrelated with the surface activity index. Conclusions: Cholestasis an d bile acids diminish the biological activity of interferon and natura l killer activity. The results suggest a decrease in the antiviral def enses in cholestatic conditions.