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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Wissenschaftlicher Beirat: 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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Band 391, Heft 10

Hefte

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.
  • Weitere Artikel des Autors:
  • 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.
  • Weitere Artikel des Autors:
  • De Gruyter OnlineGoogle Scholar
/ Ivo Münks
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • Weitere Artikel des Autors:
  • De Gruyter OnlineGoogle Scholar
/ Johannes G. Bode
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • Weitere Artikel des Autors:
  • De Gruyter OnlineGoogle Scholar
/ Dieter Häussinger
  • Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
  • Weitere Artikel des Autors:
  • De Gruyter OnlineGoogle Scholar
Online erschienen: 28.10.2010 | 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

Artikelinformationen

Corresponding author


Erhalten: 01.02.2010

Angenommen: 18.05.2010

Online erschienen: 28.10.2010

Erschienen im Druck: 01.10.2010


Quellenangabe: Biological Chemistry, Band 391, Heft 10, Seiten 1175–1187, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/bc.2010.108.

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