Impairment of the retinoic acid-inducible gene-I-IFN-β signaling pathway in chronic hepatitis B virus infection.
Impairment of the retinoic acid-inducible gene-I-IFN-β signaling pathway in chronic hepatitis B virus infection.
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DOI：
10.3892/ijmm.2012.1131
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发表时间：
2012-12
影响因子：
5.4
通讯作者：
Gang-de Zhao;B. An;Hui-juan Zhou;Hui Wang;Yumin Xu;X. Xiang;Zhi-xia Dong;F. An;Dongshan Yu;Wei-jing Wang;S. Bao;Q. Xie
中科院分区：
文献类型：
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作者：
Gang-de Zhao;B. An;Hui-juan Zhou;Hui Wang;Yumin Xu;X. Xiang;Zhi-xia Dong;F. An;Dongshan Yu;Wei-jing Wang;S. Bao;Q. Xie
慢性B型肝炎（CH B）病毒感染是由宿主免疫功能低下引起的，但确切的潜在机制仍不清楚。视黄酸诱导基因I（RIG-I）通过在病毒感染后诱导干扰素-β（IFN-β）产生来触发抗病毒免疫。为了研究RIG-I-IFN-β信号通路在CHB感染期间单核细胞衍生的树突状细胞（moDC）中的作用，通过体外刺激CD 14+单核细胞产生moDC。用水泡性口炎病毒（VSV）攻击来自CH B患者、急性肝炎B（AHB）和健康对照（HC）的MoDC，并测定刺激的moDC中RIG-1、IFN-β启动子刺激因子1（IPS-1）和IFN-β的水平。VSV刺激16小时后，相对于HC moDC，来自CHB患者的moDC中RIG-I表达降低50%，来自AHB患者的moDC中RIG-I表达降低70%，同时相对于AHB患者和HC，CHB患者中IFN-β表达降低20%。此外，观察到RIG-I/IPS-1比率与丙氨酸氨基转移酶（ALT）水平之间的显著相关性。为了进一步研究RIG-1在慢性B型肝炎病毒（HBV）感染中的功能，在RIG-1转染后用VSV攻击HepG 2或HepG2.2.15（HBV转化的）细胞系。IFN-β诱导在HepG2.2.15细胞中受到抑制，但在RIG-I转染后恢复。总之，这些数据表明CHB患者中受损的moDC功能可归因于受损的RIG-I-IFN-β信号传导途径，其导致易感人群中受损的宿主病毒清除和HBV持续存在。
Chronic hepatitis B (CHB) virus infection is caused by compromised host immunity, but the precise underlying mechanism remains unclear. Retinoic acid-inducible gene I (RIG-I) triggers antiviral immunity by inducing interferon-β (IFN-β) production following viral infection. To investigate the role of the RIG-I-IFN-β signaling pathway in monocyte-derived dendritic cells (moDCs) during CHB infection, moDCs were generated by stimulating CD14+ monocytes in vitro. MoDCs from patients with CHB, acute hepatitis B (AHB) and healthy controls (HCs) were challenged with vesicular stomatitis virus (VSV) and the levels of RIG-I, IFN-β promoter stimulator 1 (IPS-1) and IFN-β in the stimulated moDCs were determined. Following 16 h of VSV stimulation, RIG-I expression was reduced by 50% in moDCs from CHB patients and by 70% in moDCs from AHB patients relative to HC moDCs, concomitant with a 20% decrease in IFN-β expression in CHB patients relative to AHB patients and HCs. Additionally, a significant correlation between the RIG-I/IPS-1 ratio and alanine aminotransferase (ALT) level was observed. To further investigate the function of RIG-I in chronic hepatitis B virus (HBV) infection, HepG2 or HepG2.2.15 (HBV-transformed) cell lines were challenged with VSV following RIG-1 transfection. IFN-β induction was suppressed in HepG2.2.15 cells, but was restored following RIG-I transfection. Taken together, these data indicate that compromised moDC function in CHB patients is attributable to an impaired RIG-I-IFN-β signaling pathway, which results in compromised host viral clearance and HBV persistence in a susceptible population.