乙型肝炎病毒e抗原抑制死亡受体介导的肝细胞凋亡。

StephenW

Am J Pathol. 2019 Aug 23. pii: S0002-9440(19)30670-4. doi: 10.1016/j.ajpath.2019.07.014. [Epub ahead of print]
Repression of death receptor-mediated apoptosis of hepatocytes by Hepatitis B virus e antigen.
Liu W1, Guo TF2, Jing ZT3, Tong QY4.
Author information

1
    Institute of Digestive Disease, China Three Gorges University, Yichang, China; Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China. Electronic address: [email protected].
2
    Institute of Digestive Disease, China Three Gorges University, Yichang, China.
3
    Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
4
    Institute of Digestive Disease, China Three Gorges University, Yichang, China; Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China. Electronic address: [email protected].

Abstract

Hepatitis B virus (HBV) e antigen (HBeAg) is considered to associate with viral persistence and pathogenesis. Resistance of HBV-infected hepatocytes to apoptosis is seen as one of the primary promotors for HBV chronicity and malignancy. Fas receptor/ligand (Fas/FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) system plays a key role in hepatic death during HBV infection. We find here that HBeAg mediates resistance of hepatocytes to FasL or TRAIL-induced apoptosis. Introduction of HBeAg into human hepatocytes rendered resistance to FasL or TRAIL cytotoxicity in a p53-dependent manner. HBeAg further inhibited the expression of p53, total Fas, membrane-bound Fas, TNF receptor superfamily member 10a (DR4), and TNF receptor superfamily member 10b (DR5) at both mRNA and protein levels. In contrast, HBeAg enhanced the expression of soluble forms of Fas through facilitation of Fas alternative mRNA splicing. In a mouse model, expression of HBeAg in mice injected with recombinant adenovirus-associated virus 8 inhibited agonistic anti-Fas antibody (Jo2)-induced hepatic apoptosis. Xenograft tumorigenicity assay also showed that HBeAg-induced carcinogenesis was resistant to the pro-apoptotic effect of TRAIL and chemotherapeutic drugs. These results indicate that HBeAg may prevent hepatocytes from FasL and TRAIL-induced apoptosis by regulating the expression of pro-apoptotic and anti-apoptotic form of death receptors, which may contribute to the survival and persistence of infected hepatocytes during HBV infection.

Copyright © 2019. Published by Elsevier Inc.

PMID:
    31449776
DOI:
    10.1016/j.ajpath.2019.07.014

StephenW

Am J Pathol。 2019年8月23日.pii：S0002-9440（19）30670-4。 doi：10.1016 / j.ajpath.2019.07.014。 [印刷前的电子版]
乙型肝炎病毒e抗原抑制死亡受体介导的肝细胞凋亡。
刘W1，郭TF2，荆ZT3，童启四。
作者信息

1
中国三峡大学消化病研究所，宜昌;宜昌市中心人民医院消化内科，宜昌电子地址：[email protected]。
2
中国三峡大学消化病研究所，宜昌，中国。
3
福建医科大学肿瘤微生物学重点实验室，福州
4
中国三峡大学消化病研究所，宜昌;宜昌市中心人民医院消化内科，宜昌电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）e抗原（HBeAg）被认为与病毒持续性和发病机制有关。 HBV感染的肝细胞对细胞凋亡的抗性被认为是HBV慢性和恶性肿瘤的主要启动子之一。 Fas受体/配体（Fas / FasL）和肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）系统在HBV感染期间的肝脏死亡中起关键作用。我们在这里发现HBeAg介导肝细胞对FasL或TRAIL诱导的细胞凋亡的抗性。将HBeAg引入人肝细胞中以p53依赖性方式对FasL或TRAIL细胞毒性产生抗性。 HBeAg进一步抑制p53，总Fas，膜结合Fas，TNF受体超家族成员10a（DR4）和TNF受体超家族成员10b（DR5）的表达。相反，HBeAg通过促进Fas替代增强Fas可溶性形式的表达mRNA剪接。在小鼠模型中，重组腺病毒相关病毒8中小鼠HBeAg的表达抑制了激动性抗Fas抗体（Jo2）诱导的肝细胞凋亡。异种移植肿瘤发生率测定也表明HBeAg诱导的致癌作用对亲这些结果表明，HBeAg可通过调节促凋亡和抗细胞凋亡形式的死亡受体的表达来预防肝细胞FasL和TRAIL诱导的细胞凋亡，这可能有助于细胞的存活和持久性。 HBV感染期间感染的肝细胞。

版权所有©2019。由Elsevier Inc.出版

结论：
31449776
DOI：
10.1016 / j.ajpath.2019.07.014