Identification Of Interleukin1 Beta 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 (IFN alpha)-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 IFN alpha-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 IFN alpha-induced antiviral genes. Co-stimulation experiments with different pro-inflammatory cytokines revealed that this amplified expression dynamics of the early, intermediate and late IFN alpha-induced antiviral genes can also be achieved by co-application of IFN alpha and interleukin1 beta (IL1 beta). Consistently, we found that IL1 beta enhances IFN alpha-mediated repression of viral replication. Conversely, we observed that in IL1 beta receptor knock-out mice replication of viruses sensitive to IFN alpha is increased. Thus, IL1 beta is capable to potentiate IFN alpha-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 (IFN alpha)-mediated antiviral responses is an important component. However, IFN alpha 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 IFN alpha-induced antiviral genes. Knock-down of IRF2 resulted in the amplified IFN alpha-mediated induction of the antiviral genes and this amplified expression of antiviral genes could be functionally mimicked by co-stimulation with IFN alpha and IL1 beta. We observed that co-stimulation with IFN alpha and IL1 beta 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 IFN alpha. In sum, our studies identified IL1 beta as an important amplifier of IFN alpha-induced antiviral responses.