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

Robichon, Katharina and Maiwald, Tim and Schilling, Marcel and Schneider, Annette and Willemsen, Joschka and Salopiata, Florian and Teusel, Melissa and Kreutz, Clemens and Ehlting, Christian and Huang, Jun and Chakraborty, Sajib and Huang, Xiaoyun and Damm, Georg and Seehofer, Daniel and Lang, Philipp A and Bode, Johannes G and Binder, Marco and Bartenschlager, Ralf and 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

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