Bile acids modulate the interferon signalling pathway.
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.
Podevin
P
P
INSERM U402, Paris, France.
Rosmorduc
O
O
Conti
F
F
Calmus
Y
Y
Meier
P J
PJ
Poupon
R
R
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents; D001647:Bile Acids and Salts / Q000494:pharmacology*; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D006224:Cricetinae; D053938:DNA Fragmentation; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms; D008954:Models, Biological; D064547:Myxovirus Resistance Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D027981:Symporters; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D011506:Proteins; D011994:Recombinant Proteins; D027981:Symporters; D002635:Chenodeoxycholic Acid; C071908:sodium-bile acid cotransporter; D015088:2',5'-Oligoadenylate Synthetase; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate