We have previously shown that cholestasis and bile acids inhibit 2',5' olig
oadenylate synthetase (OAS) activity in the liver and in primary hepatocyte
cultures. Here, we assessed the influence of bile acids on interferon (IFN
) pathway activation in three hepatoma cell lines. In HepG2 cells, bile aci
ds (100-200 mu mol/L) inhibited IFN-induced 2',5' OAS activity to an extent
depending on their surface activity index. In Western blot analysis, IFN-i
nduced expression of two major antiviral proteins, MxA and OAS p100, was re
duced by 54% +/- 8% and 44% +/- 12%, respectively, when cells were preincub
ated for 4 hours with 100 mu mol/L chenodeoxycholic acid (CDCA). In the sam
e conditions, CDCA did not modify the IFN-induced signal transducers and ac
tivators of transcription (STAT)s tyrosine phosphorylation. In contrast, it
reduced IFN-induced MxA promoter activity by 60%. The inhibitory effect of
CDCA was not mediated by a 4 beta-phorbol 12 beta-myristate 13 alpha-aceta
te (PMA)-sensitive protein kinase C (PKC)-dependent pathway. Finally, using
CHO cells stably expressing a functional human bile acid carrier (Na+-depe
ndent taurocholate cotransporting polypeptide [NTCP]), we found that bile a
cid inhibition of the IFN pathway occurred in the range of more physiologic
al concentrations (12-50 mu mol/L). In summary, our results Provide strong
evidence that bile acids inhibit the induction of proteins involved in the
antiviral activity of IFN. This might partly explain the lack of responsive
ness to IFN therapy in some patients with. advanced chronic viral liver dis
eases.