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乙型肝炎病毒通过增加肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体1/死亡受体4的表达来增强TRAIL的细胞毒性。

Hepatitis B virus enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity by increasing TRAIL-R1/death receptor 4 expression.

作者信息

Janssen Harry L A, Higuchi Hajime, Abdulkarim Ahmad, Gores Gregory J

机构信息

Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

出版信息

J Hepatol. 2003 Sep;39(3):414-20. doi: 10.1016/s0168-8278(03)00265-4.

DOI:10.1016/s0168-8278(03)00265-4
PMID:12927928
Abstract

BACKGROUND/AIMS: Apoptosis by death receptors, such as Fas and tumor necrosis factor (TNF)-alpha receptor-1, play a significant role in the pathogenesis of hepatitis B virus (HBV)-infections. Although liver also expresses death receptors for TNF-related apoptosis-inducing ligand (TRAIL), information is lacking regarding the effects of HBV on apoptosis by TRAIL. Thus, the aims of this study were to examine the effects of HBV replication on TRAIL cytotoxicity.

METHODS

Hep G2 and Hep G2.215 cells, the latter which is stably transfected with HBV, were employed for these studies.

RESULTS

TRAIL-mediated cell killing was concentration-dependent and greater in Hep G2.2.15 cells at all doses as compared to the parent cell line, Hep G2 cells. Cell death by apoptosis was confirmed by demonstrating caspase activation and inhibition of cell killing by a caspase inhibitor, zVAD-fmk. TRAIL-R1/DR4 protein expression was enhanced in Hep G2.2.15 cells as compared to Hep G2 cells. Lamivudine treatment reduced TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression in Hep G2.2.15 cells. In Hep G2 cells transfected with the HBV-encoded X antigen (HBxAg), sensitivity to TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression were both increased.

CONCLUSIONS

TRAIL-induced apoptosis is enhanced by the level of HBV replication in human hepatocytes, in part, by HBxAg-dependent upregulation of TRAIL-R1/DR4.

摘要

背景/目的：由死亡受体介导的细胞凋亡，如Fas和肿瘤坏死因子（TNF）-α受体-1，在乙型肝炎病毒（HBV）感染的发病机制中发挥重要作用。虽然肝脏也表达肿瘤坏死因子相关凋亡诱导配体（TRAIL）的死亡受体，但关于HBV对TRAIL介导的细胞凋亡的影响尚缺乏相关信息。因此，本研究的目的是探讨HBV复制对TRAIL细胞毒性的影响。

方法

本研究采用Hep G2细胞和稳定转染HBV的Hep G2.215细胞。

结果

TRAIL介导的细胞杀伤具有浓度依赖性，在所有剂量下，与亲代细胞系Hep G2细胞相比，Hep G2.2.15细胞中的细胞杀伤作用更强。通过证明半胱天冬酶激活以及半胱天冬酶抑制剂zVAD-fmk对细胞杀伤的抑制作用，证实了细胞凋亡导致的细胞死亡。与Hep G2细胞相比，Hep G2.2.15细胞中TRAIL-R1/DR4蛋白表达增强。拉米夫定治疗可降低Hep G2.2.15细胞中TRAIL介导的细胞凋亡以及TRAIL-R1/DR4表达。在转染了HBV编码的X抗原（HBxAg）的Hep G2细胞中，对TRAIL介导的细胞凋亡的敏感性以及TRAIL-R1/DR4表达均增加。

结论

TRAIL诱导的细胞凋亡在人肝细胞中因HBV复制水平而增强，部分原因是HBxAg依赖性上调TRAIL-R1/DR4。

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