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Bile acids modulate the interferon signalling pathway
P Podevin1, O Rosmorduc, F Conti
1INSERM U402, Paris, France.
Abstract:
We have previously shown that cholestasis and bile acids inhibit 2', 5' oligoadenylate 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 acids (100-200 micromol/L) inhibited IFN-induced 2',5' OAS activity to an extent depending on their surface activity index. In Western blot analysis, IFN-induced expression of two major antiviral proteins, MxA and OAS p100, was reduced by 54% +/- 8% and 44% +/- 12%, respectively, when cells were preincubated for 4 hours with 100 micromol/L chenodeoxycholic acid (CDCA). In the same conditions, CDCA did not modify the IFN-induced signal transducers and activators 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 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA)-sensitive protein kinase C (PKC)-dependent pathway. Finally, using CHO cells stably expressing a functional human bile acid carrier (Na+-dependent taurocholate cotransporting polypeptide [NTCP]), we found that bile acid inhibition of the IFN pathway occurred in the range of more physiological concentrations (12-50 micromol/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 responsiveness to IFN therapy in some patients with advanced chronic viral liver diseases.
Insights
Bile acids, common in liver disease, were found to inhibit the interferon (IFN) pathway, reducing antiviral protein production. This may explain why some patients with chronic viral liver diseases do not respond to IFN therapy.
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Cholestasis and bile acids are known to inhibit 2', 5' oligoadenylate synthetase (OAS) activity in liver cells.
- The impact of bile acids on the broader interferon (IFN) pathway activation in liver cells remained unclear.
Purpose of the Study:
- To investigate the influence of bile acids on interferon (IFN) pathway activation in hepatoma cell lines.
- To determine the mechanism by which bile acids affect IFN-induced antiviral protein expression.
- To assess the relevance of these findings at physiological bile acid concentrations.
Main Methods:
- Hepatoma cell lines (HepG2) and engineered CHO cells expressing human NTCP were treated with bile acids.
- IFN-induced 2',5' OAS activity, MxA and OAS p100 protein expression (Western blot), STATs tyrosine phosphorylation, and MxA promoter activity were measured.
- The role of protein kinase C (PKC) and the Na+-dependent taurocholate cotransporting polypeptide (NTCP) transporter were investigated.
Main Results:
- Bile acids inhibited IFN-induced 2',5' OAS activity and the expression of antiviral proteins MxA and OAS p100 in HepG2 cells.
- Chenodeoxycholic acid (CDCA) reduced MxA promoter activity by 60% but did not affect STATs tyrosine phosphorylation.
- Inhibition of the IFN pathway by bile acids was observed at physiological concentrations (12-50 micromol/L) in NTCP-expressing cells.
Conclusions:
- Bile acids significantly inhibit the induction of key proteins involved in the antiviral activity of interferon.
- This inhibitory effect, particularly at physiological concentrations, may contribute to the reduced responsiveness to interferon therapy observed in patients with advanced chronic viral liver diseases.
- Further research into bile acid modulation of the IFN pathway could lead to improved therapeutic strategies for viral liver diseases.