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Journal of Virology, April 2009, p. 3298-3311, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02167-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Oncostatin M Enhances the Antiviral Effects of Type I Interferon and Activates Immunostimulatory Functions in Liver Epithelial Cells

Esther Larrea,^1* Rafael Aldabe,¹ Iranzu Gonzalez,^1,2 Victor Segura,³ Pablo Sarobe,¹ Itziar Echeverria,¹ and Jesus Prieto^1,4*

Division of Hepatology and Gene Therapy,¹ Bioinformatic Unit, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain,³ Digna Biotech, Pamplona 31008, Spain,² Liver Unit and CIBER-EHD, University Clinic, University of Navarra, Pamplona 31008, Spain⁴

Received 14 October 2008/ Accepted 15 January 2009

Oncostatin M (OSM) is released together with type I interferon (IFN) by activated dendritic cells, suggesting a concerted action of these cytokines in the biological response against infection. We found that OSM increases the antiviral effect of IFN- in Huh7 hepatoma cells infected with hepatitis A or hepatitis C virus and synergizes with IFN- in the induction of antiviral genes. The combination of OSM and IFN- led to upregulation of both STAT1 and STAT3 together with intense and prolonged activation of STAT1, STAT3, and Jak1. OSM with or without IFN- also activated p38 mitogen-activated protein kinase, which is known to enhance transcription of IFN--inducible genes. Interestingly, OSM combined with IFN- strongly induced immunoproteasome genes and other genes involved in antigen processing and presentation. Moreover, OSM, alone or in combination with IFN-, upregulated relevant innate immunity molecules and increased the expression of intracellular adhesion molecule 1 and interleukin-15 receptor alpha (IL-15R) in liver cells. Hepatoma cells transfected with a plasmid encoding a viral antigen were able to activate effector T cells when pretreated with IFN- plus OSM but not with each cytokine separately. Also, OSM, more than IFN-, augmented the ability of Huh7 cells to transpresent IL-15 to responding lymphocytes and increased the immunostimulatory activity of liver epithelial cells by presenting a short viral peptide to sensitized cytotoxic T cells. In conclusion, OSM enhances the antiviral effects of type I interferon and cooperates with it in the induction of adaptive immune responses to pathogens. These findings may have therapeutic implications.

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* Corresponding author. Mailing address: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, and University Clinic, University of Navarra, Avda. Pio XII 55, 31008 Pamplona, Navarra, Spain. Phone: 34-948194700 or 34-296785. Fax: 34-948194717. E-mail for E. Larrea: elarrea{at}unav.es. E-mail for J. Prieto: jprieto{at}unav.es

Published ahead of print on 21 January 2009.

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Journal of Virology, April 2009, p. 3298-3311, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02167-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.