The Effect of Tumor Necrosis Factor-related Apoptosis-inducing Ligand on the Self-promoter of Hepatitis B Virus_West China Medical Journal

Authors：

WU Dongbo ¹ , LIU Fanwei ¹ , TANG Hong ¹ , ZHAO Liansan ¹ , YAN Jufang ² , CHEN Shouchun ² ,  ZHOU Taoyou ¹

1. Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China; 2. Genetic Engineering Laboratory, Chengdu Diao Group Co. Ltd, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

ZHOU Taoyou, Email: wudongbo452@yahoo.com

Keywords：

肿瘤坏死因子凋亡诱导配体; 乙型肝炎病毒; 自身启动子; 相对荧光素酶活性

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目的　肿瘤坏死因子相关凋亡诱导配体（TRAIL）能够诱导乙型肝炎病毒（HBV）感染细胞发生凋亡，但抑制病毒复制的具体机制不清楚，研究通过非凋亡浓度TRAIL对4种HBV启动子调控作用的研究，探讨HBV复制的可能调控机制。方法　采用噻唑蓝法和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记荧光法，检测不同浓度TRAIL作用后人肝癌细胞株HepG2的存活率。使用HBV的4种启动子重组质粒，4种启动子分别控制乙肝表面抗原、X抗原、核心抗原、PS1抗原基因的转录与表达。将受HBV上述4种启动子调控的荧光素酶报道基因表达质粒（SpLUC、XpLUC、CpLUC、PS1pLUC）转染HepG2细胞，6 h后按300 、30 、3 ng/mL浓度梯度加入可溶性TRAIL，采用双荧光报道基因分析系统检测细胞化学发光值，计算相对荧光素酶活性。结果　300 ng/mL是可溶性TRAIL诱导HepG2细胞凋亡的浓度阈值。采用远低于凋亡阈值浓度（30 ng/mL）的TRAIL可明显上调对HBV的 Sp启动子活性（P＜0.001），另3种质粒的相对荧光素酶活性在加入TRAIL后改变不大。结论　TRAIL仅对HBV的 Sp启动子活性具有上调作用，其生物学意义值得进一步研究。

Citation： WU Dongbo,LIU Fanwei,TANG Hong,ZHAO Liansan,YAN Jufang,CHEN Shouchun,ZHOU Taoyou. The Effect of Tumor Necrosis Factor-related Apoptosis-inducing Ligand on the Self-promoter of Hepatitis B Virus. West China Medical Journal, 2012, 27(11): 1601-1605. doi: Copy

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2.	Pan G, O’Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL[J]. Science, 1997, 276(5309): 111-113.
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6.	Mundt B, Kühnel F, Zender L, et al. Involvement of TRAIL and its receptors in viral hepatitis[J]. FASEB J, 2003, 17(1): 94-96.
7.	Tang H, Delgermaa L, Huang F, et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication[J]. J Virol, 2005, 79(9): 5548-5556.
8.	Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity, 1995, 3(6): 673-682.
9.	Daniels RA, Turley H, Kimberley FC, et al. Expression of TRAIL and TRAIL receptors in normal and malignant tissues[J]. Cell Res, 2005, 15(6): 430-438.
10.	Warke RV, Martin KJ, Giaya K, et al. TRAIL is a novel antiviral protein against dengue virus[J]. J Virol, 2008, 82(1): 555-564.
11.	Shrestha B, Pinto AK, Green S, et al. CD8+ T cells use TRAIL to restrict West Nile virus pathogenesis by controlling infection in neurons[J]. J Virol, 2012, 86(17): 8937-8948.
12.	Han LH, Sun WS, Ma CH, et al. Detection of soluble TRAIL in HBV infected patients and its clinical implications[J]. World J Gastroenterol, 2002, 8(6): 1077-1080.
13.	Raney AK, Johnson JL, Palmer CN, et al. Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter[J]. J Virol,1997, 71(2): 1058-1071.
14.	Beck J, Nassal M. Hepatitis B virus replication[J]. World J Gastroenterol, 2007, 13(1): 48-64.
15.	Lu CC, Chen M, Ou JH, et al. Key role of a CCAAT element in regulating hepatitis B virus surface protein expression[J]. Virology, 1995, 206(2): 1155-1158.
16.	Quasdorff M, Protzer U. Control of hepatitis B virus at the level of transcription[J]. J Viral Hepat, 2010, 17(8): 527-536.

1. 　Das A, Maini MK. Innate and adaptive immune responses in hepatitis B virus infection[J]. Dig Dis, 2010, 28(1): 126-132.
2. 　Pan G, O’Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL[J]. Science, 1997, 276(5309): 111-113.
3. 　Kim Y, Seol DW. TRAIL, a mighty apoptosis inducer[J]. Mol Cells, 2003, 15(3): 283-293.
4. 　Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors[J]. Oncogene, 2003, 22(53): 8628-8633.
5. 　Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy[J]. Nat Rev Cancer, 2008, 8(10): 782-798.
6. 　Mundt B, Kühnel F, Zender L, et al. Involvement of TRAIL and its receptors in viral hepatitis[J]. FASEB J, 2003, 17(1): 94-96.
7. 　Tang H, Delgermaa L, Huang F, et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication[J]. J Virol, 2005, 79(9): 5548-5556.
8. 　Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity, 1995, 3(6): 673-682.
9. 　Daniels RA, Turley H, Kimberley FC, et al. Expression of TRAIL and TRAIL receptors in normal and malignant tissues[J]. Cell Res, 2005, 15(6): 430-438.
10. 　Warke RV, Martin KJ, Giaya K, et al. TRAIL is a novel antiviral protein against dengue virus[J]. J Virol, 2008, 82(1): 555-564.
11. 　Shrestha B, Pinto AK, Green S, et al. CD8+ T cells use TRAIL to restrict West Nile virus pathogenesis by controlling infection in neurons[J]. J Virol, 2012, 86(17): 8937-8948.
12. 　Han LH, Sun WS, Ma CH, et al. Detection of soluble TRAIL in HBV infected patients and its clinical implications[J]. World J Gastroenterol, 2002, 8(6): 1077-1080.
13. 　Raney AK, Johnson JL, Palmer CN, et al. Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter[J]. J Virol,1997, 71(2): 1058-1071.
14. 　Beck J, Nassal M. Hepatitis B virus replication[J]. World J Gastroenterol, 2007, 13(1): 48-64.
15. 　Lu CC, Chen M, Ou JH, et al. Key role of a CCAAT element in regulating hepatitis B virus surface protein expression[J]. Virology, 1995, 206(2): 1155-1158.
16. 　Quasdorff M, Protzer U. Control of hepatitis B virus at the level of transcription[J]. J Viral Hepat, 2010, 17(8): 527-536.

West China Medical Journal

The Effect of Tumor Necrosis Factor-related Apoptosis-inducing Ligand on the Self-promoter of Hepatitis B Virus

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