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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

SCImago Journal Rank (SJR) 2018: 1.482
Source Normalized Impact per Paper (SNIP) 2018: 0.820

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1437-4315
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Volume 391, Issue 10

Issues

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

Dirk Graf
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • These authors contributed equally to this work.
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Katrin Haselow
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • These authors contributed equally to this work.
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ivo Münks
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Johannes G. Bode
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Dieter Häussinger
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2010-10-28 | DOI: https://doi.org/10.1515/bc.2010.108

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

About the article

Corresponding author


Received: 2010-02-01

Accepted: 2010-05-18

Published Online: 2010-10-28

Published in Print: 2010-10-01


Citation Information: Biological Chemistry, Volume 391, Issue 10, Pages 1175–1187, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/bc.2010.108.

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