Ma Li, Zhou Yun, Zhang Ying, Li Yuan, Guo Yonghong, He Yu, Wang Jiuping, Lian Jianqi, Hao Chunqiu, Moorman Jonathan P, Yao Zhi Q, Zhou Yongxing, Jia Zhansheng
Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Immunology. 2014 Dec;143(4):670-8. doi: 10.1111/imm.12350.
Hepatitis C virus (HCV) infection is a global health problem characterized by a high rate of chronic infection, which may in part be due to a defect in myeloid dendritic cells (mDCs). This defect appears to be remedied by treatment with interferon-α (IFN-α) -based antiviral therapies; however, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear. The ubiquitin-editing protein A20 plays a crucial role in controlling the maturation, cytokine production and immunostimulatory function of mDCs. We propose that the expression of A20 correlates with the function of mDCs during HCV infection and IFN-α therapy. In this study, we observed that A20 expression in mDCs isolated from chronically HCV-infected subjects was significantly higher than healthy subjects or subjects achieving sustained virological responses (SVR) following antiviral treatment. Notably, A20 expression in mDCs from HCV patients during IFN-α treatment was significantly lower than for untreated patients, SVR patients, or healthy subjects. Besides, A20 expression in mDCs stimulated by polyI:C differed between HCV patients and healthy subjects, and this difference could be abrogated by the treatment with IFN-α in vitro. Additionally, A20 expression by polyI:C-activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of HLA-DR, CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Importantly, silencing A20 expression using small interfering RNAs increased the production of IL-12 in mDCs of chronically HCV-infected individuals. These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection.
丙型肝炎病毒（HCV）感染是一个全球性的健康问题，其特征是慢性感染率高，这可能部分归因于髓样树突状细胞（mDC）的缺陷。这种缺陷似乎可以通过基于干扰素-α（IFN-α）的抗病毒疗法得到纠正；然而，HCV感染中mDC功能障碍以及IFN-α治疗恢复其功能的潜在分子机制尚不清楚。泛素编辑蛋白A20在控制mDC的成熟、细胞因子产生和免疫刺激功能方面起着关键作用。我们提出，在HCV感染和IFN-α治疗期间，A20的表达与mDC的功能相关。在本研究中，我们观察到，从慢性HCV感染受试者分离的mDC中A20的表达显著高于健康受试者或抗病毒治疗后实现持续病毒学应答（SVR）的受试者。值得注意的是，在IFN-α治疗期间，HCV患者mDC中A20的表达显著低于未治疗患者、SVR患者或健康受试者。此外，HCV患者和健康受试者中受聚肌胞苷酸（polyI:C）刺激的mDC中A20的表达存在差异，并且这种差异可在体外通过IFN-α治疗消除。此外，无论是否进行IFN-α治疗，polyI:C激活的mDC中A20的表达与HLA-DR、CD86和CCR7的表达以及白细胞介素-12（IL-12）的分泌呈负相关，但与IL-10的产生呈正相关。重要的是，使用小干扰RNA沉默A20表达可增加慢性HCV感染个体mDC中IL-12的产生。这些发现表明，A20在慢性病毒感染期间对先天免疫应答的负调控中起关键作用。
