Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication

Abstract

The interferon (IFN)-related cytokine interleukin (IL)-29 (also known as IFN-λ1) inhibits virus replication by inducing a cellular antiviral response similar to that activated by IFN-α/β. However, because it binds to a unique receptor, this cytokine may function cooperatively with IFN-α/β or IFN-γ during natural infections to inhibit virus replication, and might also be useful therapeutically in combination with other cytokines to treat chronic viral infections such as hepatitis C (HCV). We therefore investigated the ability of IL-29 and IFN-α or IFN-γ to cooperatively inhibit virus replication and induce antiviral gene expression. Compared with the individual cytokines alone, the combination of IL-29 with IFN-α or IFN-γ was more effective at blocking vesicular stomatitis virus and HCV replication, and this cooperative antiviral activity correlated with the magnitude of induced antiviral gene expression. Although the combined effects of IL-29 and IFN-α were primarily additive, the IL-29/IFN-γ combination synergistically induced multiple genes and had the greatest antiviral activity. Two different mechanisms contributed to the enhanced gene expression induced by the cytokine combinations: increased activation of ISRE promoter elements and simultaneous activation of both ISRE and GAS elements within the same promoter. These findings provide new insight into the coregulation of a critical innate immune response by functionally distinct cytokine families. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.