Bile acids modulate the interferon signalling pathway

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.