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Inhibition of interferon-α-induced signaling by hyperosmolarity and hydrophobic bile acids

  • Dirk Graf , Katrin Haselow , Ivo Münks , Johannes G. Bode and Dieter Häussinger
Published/Copyright: October 28, 2010
Biological Chemistry
From the journal Volume 391 Issue 10

Abstract

Apart from viral conditions, host factors such as elevated bile acid concentrations are determinants of successful interferon-α (IFN-α) treatment in patients with chronic hepatitis C or B. The present study demonstrates that hydrophobic bile acids inhibit Jak1- and Tyk2-phosphorylation, which lead to blockade of STAT1-mediated IFN-α-signaling in the sodium-taurocholate cotransporting peptide (NTCP)-transfected human hepatoma cell line HepG2, resulting in a decreased mRNA and protein expression of IFN-stimulated genes such as myxovirus resistance protein A (MxA) or dsRNA-activated protein kinase (PKR). In addition, hyperosmotic stress leads to an inhibition of IFN-α-induced Jak1- and Tyk2-phosphorylation, and STAT1/STAT2-phosphorylation and gene expression. This inhibitory effect of hydrophobic bile acids or hyperosmolarity is not due to caspase-mediated cleavage or lysosomal degradation of the cognate receptors or to the generation of oxidative stress, activation of p38- or Erk-mediated MAPK pathways or phosphatase activity. Preincubation with the organic osmolyte betaine blocked the inhibitory effect of bile acids or hyperosmolarity on MxA protein expression, but had no effect on transcript levels or activation of STAT1, suggesting that betaine mediates its effects on MxA expression at a translational or post-translational level. Our findings could provide a rationale for betaine use in cholestatic HBV/HCV patients undergoing interferon therapy.

Keywords: glycochenodeoxycholate; hepatitis C; myxovirus resistance protein A (MxA); osmolyte; STAT
Corresponding author
Received: 2010-2-1
Accepted: 2010-5-18
Published Online: 2010-10-28
Published in Print: 2010-10-01

©2010 by Walter de Gruyter Berlin New York

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https://doi.org/10.1515/bc.2010.108
Keywords for this article
glycochenodeoxycholate; hepatitis C; myxovirus resistance protein A (MxA); osmolyte; STAT

Articles in the same Issue

  1. Guest Editorial
  2. Highlight: The Biology of Aging: Mechanisms and Intervention
  3. Highlight: 61th Mosbach Colloquium of the GBM ‘The Biology of Aging: Mechanisms and Intervention’
  4. Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants
  5. The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging
  6. E. coli hypoxia-inducible factor ArcA mediates lifespan extension in a lipoic acid synthase mutant by suppressing acetyl-CoA synthetase
  7. Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis
  8. PROTEIN STRUCTURE AND FUNCTION
  9. New structural aspects of FKBP38 activation
  10. The neuronal proteins CIPP, Cypin and IRSp53 form a tripartite complex mediated by PDZ and SH3 domains
  11. CELL BIOLOGY AND SIGNALING
  12. Inhibition of interferon-α-induced signaling by hyperosmolarity and hydrophobic bile acids
  13. Role of the second disulfide bridge (Cys18-Cys274) in stabilizing the inactive AT1 receptor
  14. Demonstration of protein absorption in the intestinal epithelium of fish and mice by laser scanning confocal microscopy
  15. Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J mice
  16. PROTEOLYSIS
  17. Amino acid residues modulating the activities of staphylococcal glutamyl endopeptidases
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