IFN- α 5 Mediates Stronger Tyk2-Stat-Dependent Activation and Higher Expression of 2′,5′-Oligoadenylate Synthetase Than IFN- α 2 in Liver Cells

Abstract

Interferon-α5 (IFN-α5) is the main IFN-α subtype expressed in the liver. Hepatitis C virus (HCV) infection is associated with low IFN-α5 mRNA levels, possibly reflecting an escape mechanism of the virus. In this work, we sought to compare IFN-α2 and IFN-α5 with respect to activation of early cell signaling cascades and induction of antiviral genes in the human hepatoma HepG2 and Huh7 cell lines. We found that the Tyr⁷⁰¹ phosphorylation kinetics of Stat1 mediated by IFN stimulation was higher when cells were incubated with IFN-α5 than when using IFN-α2. Similarly, Tyr^1054/1055 phosphorylation kinetics of Tyk2 were more intense after exposure to IFN-α5 than when using IFN-α2. Concomitantly, Tyr⁷⁰⁵ phosphorylation of Stat3 was higher after stimulation with IFN-α5 than with IFN-α2. In parallel to these findings, the mRNA levels of the antiviral IFN-inducible gene 2′,5′-oligoadenylate synthetase were higher in cell samples treated with IFN-α5 than with IFN-α2. These findings suggest that interaction of IFN-α5 and IFN-α2 subtypes with IFN type I receptor occurs differently, and this affects the intensity of expression of antiviral genes. In conclusion, our data show that in hepatocytic cells, IFN-α5 induces stronger signaling and higher expression of antiviral genes than IFN-α2. These data warrant clinical trials to evaluate the efficacy of IFN-α5 in chronic viral hepatitis.