Identification of Interleukin1ß as an Amplifier of Interferon alpha-induced Antiviral Responses.
PLoS Pathog
; 16(10): e1008461, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-33002089
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 (IL1ß). Consistently, we found that IL1ß enhances IFNα-mediated repression of viral replication. Conversely, we observed that in IL1ß receptor knock-out mice replication of viruses sensitive to IFNα is increased. Thus, IL1ß is capable to potentiate IFNα-induced antiviral responses and could be exploited to improve antiviral therapies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Replicação Viral
/
Regulação Viral da Expressão Gênica
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Interferon-alfa
/
Fator Regulador 2 de Interferon
/
Receptores Tipo I de Interleucina-1
/
Coriomeningite Linfocítica
/
Vírus da Coriomeningite Linfocítica
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
PLoS Pathog
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha