Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax.
Hepatitis B virus (HBV) infection afflicts >300 million people worldwide and is a leading cause of hepatocyte death, cirrhosis, and hepatocellular carcinoma. While the morphological characteristics of dying hepatocytes are well documented, the molecular mechanisms leading to the death of hepatocytes during HBV infection are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in the death of hepatocytes under certain inflammatory but not normal conditions. To determine the potential roles of TRAIL in HBV-induced hepatitis, we examined the effects of HBV and its X protein (HBx) on TRAIL-induced hepatocyte apoptosis both in vivo and in vitro. We found that hepatitis and hepatic cell death in HBV transgenic mice were significantly inhibited by a soluble TRAIL receptor that blocks TRAIL function. We also found that HBV or HBx transfection of a hepatoma cell line significantly increased its sensitivity to TRAIL-induced apoptosis. The increase in TRAIL sensitivity were associated with a dramatic up-regulation of Bax protein expression. Knocking down Bax expression using Bax-specific small interference RNA blocked HBV-induced hepatitis and hepatocyte apoptosis. The degradation of caspases 3 and 9, but not that of Bid or caspase-8, was preferentially affected by Bax knockdown. These results establish that HBV sensitizes hepatocytes to TRAIL-induced apoptosis through Bax and that Bax-specific small interference RNA can be used to inhibit HBV-induced hepatic cell death.
Liang
Xiaohong
X
Institute of Immunology, School of Medicine, Shandong University, Jinan, People's Republic of China.
Liu
Yugang
Y
Zhang
Qiu
Q
Gao
Lifen
L
Han
Lihui
L
Ma
Chunhong
C
Zhang
Lining
L
Chen
Youhai H
YH
Sun
Wensheng
W
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006509:Hepatitis B / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000502:physiology*; D015534:Trans-Activators; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051028:bcl-2-Associated X Protein; C057628:hepatitis B virus X protein; D020169:Caspases