Effect of cholestasis and bile acids on interferon-induced 2',5'-adenylate synthetase and NK cell activities.
OBJECTIVE
The mechanisms involved in resistance to interferon alfa in patients with chronic hepatitis C are unclear. Both cirrhosis and cholestasis have been shown to be predictive of resistance. The aim of this study was to evaluate the influence of cholestasis and bile acids on 2',5'-oligoadenylate synthetase and natural killer activities, which are both involved in the antiviral activity of interferon.


METHODS
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'-oligoadenylate synthetase and natural killer activities was examined in fresh mononuclear cells from healthy subjects.


RESULTS
Cholestasis had a time-dependent inhibitory effect on 2',5'-oligoadenylate synthetase activity in liver, spleen, and isolated hepatocytes from cholestatic rats (-70%, 86%, and 70% relative to baseline, respectively). In vitro, endogenous bile acids had a concentration-dependent inhibitory effect on interferon-induced 2',5'-oligoadenylate synthetase and natural killer activities, which was related to their structure. This inhibitory effect correlated with the surface activity index.


CONCLUSIONS
Cholestasis and bile acids diminish the biological activity of interferon and natural killer activity. The results suggest a decrease in the antiviral defenses in cholestatic conditions.
Podevin
P
P
INSERM Unité 402, Hôpital Saint-Antoine, Paris, France.
Calmus
Y
Y
Bonnefis
M T
MT
Veyrunes
C
C
Chereau
C
C
Poupon
R
R
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis*; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002779:Cholestasis / Q000201:enzymology* / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
D001647:Bile Acids and Salts; D016898:Interferon-alpha; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D015088:2',5'-Oligoadenylate Synthetase