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鉴定白细胞介素 1β作为干扰素 α 诱导抗病毒反应的增强剂。

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

机构信息

Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Institute for Physics, University of Freiburg, Germany.

出版信息

PLoS Pathog. 2020 Oct 1;16(10):e1008461. doi: 10.1371/journal.ppat.1008461. eCollection 2020 Oct.

DOI:10.1371/journal.ppat.1008461
PMID:33002089
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7553310/
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.

摘要

干扰素介导的反应的诱导是抵御病毒等病原体的第一道防线。然而，干扰素 alpha (IFNα)诱导的抗病毒基因的动态和程度变化显著，并包含三个表达簇：早期、中期和晚期。通过基于时间分辨定量数据的数学建模，我们确定了 mRNA 稳定性以及负反馈调节环是内源性控制肝细胞中 IFNα诱导的抗病毒基因表达动力学的关键机制。根据数学模型，我们发现该调节环由转录因子 IRF2 介导，并表明敲低 IRF2 会导致早期、中期和晚期 IFNα诱导的抗病毒基因表达增强。用不同的促炎细胞因子进行共刺激实验表明，早期、中期和晚期 IFNα诱导的抗病毒基因的这种放大表达动力学也可以通过共应用 IFNα 和白细胞介素 1β (IL1β)来实现。一致地，我们发现 IL1β 增强了 IFNα 介导的病毒复制抑制。相反，我们观察到在 IL1β 受体敲除小鼠中，对 IFNα 敏感的病毒的复制增加了。因此，IL1β 能够增强 IFNα 诱导的抗病毒反应，并可用于改善抗病毒治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49b4/7553310/a2c1e7f269fa/ppat.1008461.g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49b4/7553310/a2c1e7f269fa/ppat.1008461.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49b4/7553310/18df8221197a/ppat.1008461.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49b4/7553310/806d6f269ca9/ppat.1008461.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/49b4/7553310/a2c1e7f269fa/ppat.1008461.g008.jpg

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