Oncostatin M enhances the antiviral effects of type I interferon and activates immunostimulatory functions in liver epithelial cells.
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-alpha in Huh7 hepatoma cells infected with hepatitis A or hepatitis C virus and synergizes with IFN-alpha in the induction of antiviral genes. The combination of OSM and IFN-alpha led to upregulation of both STAT1 and STAT3 together with intense and prolonged activation of STAT1, STAT3, and Jak1. OSM with or without IFN-alpha also activated p38 mitogen-activated protein kinase, which is known to enhance transcription of IFN-alpha-inducible genes. Interestingly, OSM combined with IFN-alpha strongly induced immunoproteasome genes and other genes involved in antigen processing and presentation. Moreover, OSM, alone or in combination with IFN-alpha, upregulated relevant innate immunity molecules and increased the expression of intracellular adhesion molecule 1 and interleukin-15 receptor alpha (IL-15Ralpha) in liver cells. Hepatoma cells transfected with a plasmid encoding a viral antigen were able to activate effector T cells when pretreated with IFN-alpha plus OSM but not with each cytokine separately. Also, OSM, more than IFN-alpha, 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.
Larrea
Esther
E
Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. elarrea@unav.es
Aldabe
Rafael
R
Gonzalez
Iranzu
I
Segura
Victor
V
Sarobe
Pablo
P
Echeverria
Itziar
I
Prieto
Jesus
J
D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D030041:Hepatitis A virus / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007370:Interferon Type I / Q000276:immunology*; D019409:Interleukin-15 / Q000096:biosynthesis; D053613:Janus Kinase 1 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation; D053683:Oncostatin M / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D007370:Interferon Type I; D019409:Interleukin-15; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053683:Oncostatin M; D018799:Intercellular Adhesion Molecule-1; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases