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：

腫瘤壞死因子凋亡誘導配體; 乙型肝炎病毒; 自身啟動子; 相對熒光素酶活性

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目的　腫瘤壞死因子相關凋亡誘導配體（TRAIL）能夠誘導乙型肝炎病毒（HBV）感染細胞發生凋亡，但抑制病毒復制的具體機制不清楚，研究通過非凋亡濃度TRAIL對4種HBV啟動子調控作用的研究，探討HBV復制的可能調控機制。方法　采用噻唑藍法和末端脫氧核苷酸轉移酶介導的dUTP缺口末端標記熒光法，檢測不同濃度TRAIL作用后人肝癌細胞株HepG2的存活率。使用HBV的4種啟動子重組質粒，4種啟動子分別控制乙肝表面抗原、X抗原、核心抗原、PS1抗原基因的轉錄與表達。將受HBV上述4種啟動子調控的熒光素酶報道基因表達質粒（SpLUC、XpLUC、CpLUC、PS1pLUC）轉染HepG2細胞，6 h后按300 、30 、3 ng/mL濃度梯度加入可溶性TRAIL，采用雙熒光報道基因分析系統檢測細胞化學發光值，計算相對熒光素酶活性。結果　300 ng/mL是可溶性TRAIL誘導HepG2細胞凋亡的濃度閾值。采用遠低于凋亡閾值濃度（30 ng/mL）的TRAIL可明顯上調對HBV的 Sp啟動子活性（P＜0.001），另3種質粒的相對熒光素酶活性在加入TRAIL后改變不大。結論　TRAIL僅對HBV的 Sp啟動子活性具有上調作用，其生物學意義值得進一步研究。

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

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.

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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