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

Autor: Katharina Robichon, Tim Maiwald, Marcel Schilling, Annette Schneider, Joschka Willemsen, Florian Salopiata, Melissa Teusel, Clemens Kreutz, Christian Ehlting, Jun Huang, Sajib Chakraborty, Xiaoyun Huang, Georg Damm, Daniel Seehofer, Philipp A Lang, Johannes G Bode, Marco Binder, Ralf Bartenschlager, Jens Timmer, Ursula Klingmüller
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: PLoS Pathogens, Vol 16, Iss 10, p e1008461 (2020)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1008461
Popis: 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.
Databáze: Directory of Open Access Journals
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