Robichon, Katharina, Maiwald, Tim, Schilling, Marcel, Schneider, Annette, Willemsen, Joschka, Salopiata, Florian, Teusel, Melissa, Kreutz, Clemens, Ehlting, Christian, Huang, Jun, Chakraborty, Sajib, Huang, Xiaoyun, Damm, Georg, Seehofer, Daniel, Lang, Philipp A, Bode, Johannes G, Binder, Marco, Bartenschlager, Ralf, Timmer, Jens and Klingmüller, Ursula (2020) Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses. PLoS pathogens, 16 (10). e1008461. ISSN 1553-7374

Abstract

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.

Item Type:	Article
Date Deposited:	15 Dec 2020 00:45
Last Modified:	15 Dec 2020 00:45
URI:	https://oak.novartis.com/id/eprint/44032