Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses

The induction of an interferon-mediated response is the first line of defense against pathogens such as viruses. Yet, the dynamics and extent of interferon alpha (IFNα)-induced antiviral genes vary remarkably and comprise three expression clusters: early, intermediate and late. By mathematical modeling based on time-resolved quantitative data, we identified mRNA stability as well as a negative regulatory loop as key mechanisms endogenously controlling the expression dynamics of IFNα-induced antiviral genes in hepatocytes. Guided by the mathematical model, we uncovered that this regulatory loop is mediated by the transcription factor IRF2 and showed that knock-down of IRF2 results in enhanced expression of early, intermediate and late IFNα-induced antiviral genes. Co-stimulation experiments with different pro-inflammatory cytokines revealed that this amplified expression dynamics of the early, intermediate and late IFNα-induced antiviral genes can also be achieved by co-application of IFNα and interleukin1 beta (IL1β). Consistently, we found that IL1β enhances IFNα-mediated repression of viral replication. Conversely, we observed that in IL1β receptor knock-out mice replication of viruses sensitive to IFNα is increased. Thus, IL1β is capable to potentiate IFNα-induced antiviral responses and could be exploited to improve antiviral therapies.
Author summary Innate immune responses contribute to the control of viral infections and the induction of interferon alpha (IFNα)-mediated antiviral responses is an important component. However, IFNα induces a multitude of antiviral response genes and the expression dynamics of these genes can be classified as early, intermediate and late. Here we show, based on a mathematical modeling approach, that mRNA stability as well as the negative regulator IRF2 control the expression dynamics of IFNα-induced antiviral genes. Knock-down of IRF2 resulted in the amplified IFNα-mediated induction of the antiviral genes and this amplified expression of antiviral genes could be functionally mimicked by co-stimulation with IFNα and IL1β. We observed that co-stimulation with IFNα and IL1β enhanced the repression of virus replication and that knock-out of the IL1 receptor in mice resulted in increased replication of a virus sensitive to IFNα. In sum, our studies identified IL1β as an important amplifier of IFNα-induced antiviral responses.