IL-1β Enhances the Antiviral Effect of IFN-α on HCV Replication by Negatively Modulating ERK2 Activation.,ACS Infectious Diseases

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IL-1β Enhances the Antiviral Effect of IFN-α on HCV Replication by Negatively Modulating ERK2 Activation.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-05-18 , DOI: 10.1021/acsinfecdis.9b00506
Mingzhe Guo _{1,

2,

3} , Liqing Ye _{1,

2,

3} , Tao Yu ₁ , Lin Han _{1,

2,

3} , Qingchao Li ₁ , Peilan Lou _{1,

2,

3} , Tianyu Gan _{1,

3} , Xia Jin , Hui Xiao _{1,

3} , Guangxun Meng _{1,

3} , Jin Zhong _{1,

2,

3} , Yongfen Xu ₁

Affiliation

Chronic hepatitis C infection is a leading cause of liver cirrhosis, which is linked to chronic hepatic inflammation. While there are multiple studies detailing the proinflammatory role of interleukin-1β (IL-1β) in HCV-induced inflammasome signaling, the antiviral capacity of this cytokine has not been adequately investigated in the context of HCV infection or other members of Flaviridae. Our data indicated that IL-1β alone does not inhibit HCV replication, yet when in combination with IFN-α, it can boost the anti-HCV activity of IFN-α, which is mediated by augmented STAT1 tyrosine 701 phosphorylation. Through signaling inhibitor screening, we found that ERK2 kinase is directly linked to the enhanced activation of the STAT1 complex. Our study found that IL-1β negatively affects ERK2 phosphorylation, which suggests that IL-1β-mediated STAT1 tyrosine 701 phosphorylation employed kinase machinery of ERK2 other than JNK or P38 kinase. Our results identify IL-1β as a proinflammatory cytokine possessing wide spectrum synergistic antiviral capability via enhancing IFN-α-induced interferon-stimulated genes (ISGs) expression. A more nuanced understanding of the antiviral mechanisms of this important cytokine could facilitate the development of new therapeutic options.

中文翻译：

IL-1β通过负调节ERK2激活增强IFN-α对HCV复制的抗病毒作用。

慢性丙型肝炎感染是肝硬化的主要原因，这与慢性肝炎有关。尽管有许多研究详细说明白介素-1β（IL-1β）在HCV诱导的炎性体信号传导中的促炎作用，但在HCV感染或黄病毒科其他成员的情况下，尚未对该细胞因子的抗病毒能力进行充分研究。我们的数据表明，单独的IL-1β不能抑制HCV复制，但是当与IFN-α结合使用时，它可以增强IFN-α的抗HCV活性，这是由STAT1酪氨酸701磷酸化的增强介导的。通过信号抑制剂筛选，我们发现ERK2激酶直接与STAT1复合物的增强激活有关。我们的研究发现，IL-1β对ERK2磷酸化有负面影响，这表明IL-1β介导的STAT1酪氨酸701磷酸化采用了除JNK或P38激酶以外的ERK2激酶机制。我们的结果确定IL-1β是通过增强IFN-α诱导的干扰素刺激基因（ISGs）的表达而具有广谱协同抗病毒能力的促炎细胞因子。对这种重要细胞因子的抗病毒机制的更细微的了解可以促进新的治疗选择的发展。

更新日期：2020-07-10

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