Epidermal growth factor receptor signaling impairs the antiviral activity of interferon-alpha

Lupberger, J. and Duong, F. H. and Fofana, I. and Zona, L. and Xiao, F. and Thumann, C. and Durand, S. C. and Pessaux, P. and Zeisel, M. B. and Heim, M. H. and Baumert, T. F.. (2013) Epidermal growth factor receptor signaling impairs the antiviral activity of interferon-alpha. Hepatology, Vol. 58, No. 4. pp. 1225-1235.

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Official URL: http://edoc.unibas.ch/dok/A6338541

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Interferon-alpha (IFN-alpha) exhibits its antiviral activity through signal transducer and activator of transcription protein (STAT) signaling and the expression of IFN response genes (IRGs). Viral infection has been shown to result in activation of epidermal growth factor receptor (EGFR)-a host cell entry factor used by several viruses, including hepatitis C virus. However, the effect of EGFR activation for cellular antiviral responses is unknown. Here, we uncover cross-talk between EGFR and IFN-alpha signaling that has a therapeutic effect on IFN-alpha-based therapies and functional relevance for viral evasion and IFN resistance. We show that combining IFN-alpha with the EGFR inhibitor, erlotinib, potentiates the antiviral effect of each compound in a highly synergistic manner. The extent of the synergy correlated with reduced STAT3 phosphorylation in the presence of erlotinib, whereas STAT1 phosphorylation was not affected. Furthermore, reduced STAT3 phosphorylation correlated with enhanced expression of suppressors of cytokine signaling 3 (SOCS3) in the presence of erlotinib and enhanced expression of the IRGs, radical S-adenosyl methionine domain containing 2 and myxovirus resistance protein 1. Moreover, EGFR stimulation reduced STAT1 dimerization, but not phosphorylation, indicating that EGFR cross-talk with IFN signaling acts on the STATs at the level of binding DNA. Conclusions: Our results support a model where inhibition of EGFR signaling impairs STAT3 phosphorylation, leading to enhanced IRG expression and antiviral activity. These data uncover a novel role of EGFR signaling in the antiviral activity of IFN-alpha and open new avenues of improving the efficacy of IFN-alpha-based antiviral therapies.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)
UniBasel Contributors:Heim, Markus H.
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:14
Deposited On:10 Apr 2015 09:14

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