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

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.

• Authors: Dirk Graf, Katrin Haselow, Ivo Münks, Johannes G Bode, Dieter Häussinger
• Journal: Biological chemistry (Biol Chem) Vol. 391 Issue 10 Pg. 1175-87 (Oct 2010) ISSN: 1437-4315 [Electronic] Germany
• PMID: 21028968 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon Regulatory Factors
• Interferon-alpha
• MX1 protein, human
• Myxovirus Resistance Proteins
• STAT1 Transcription Factor
• Betaine
• Taurochenodeoxycholic Acid
• Glycochenodeoxycholic Acid
• GTP-Binding Proteins

Topics

• Betaine (pharmacology)
• GTP-Binding Proteins (genetics)
• Gene Expression Regulation (drug effects)
• Glycochenodeoxycholic Acid (chemistry, pharmacology)
• Hep G2 Cells
• Humans
• Hydrophobic and Hydrophilic Interactions
• Interferon Regulatory Factors (metabolism)
• Interferon-alpha (metabolism, pharmacology)
• Myxovirus Resistance Proteins
• Osmolar Concentration
• STAT1 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Taurochenodeoxycholic Acid (chemistry, pharmacology)