Cleaved c-FLIP mediates the antiviral effect of TNF-α against hepatitis B virus by dysregulating hepatocyte nuclear factors

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• 作者：Yong Kwang Park¹ ; ² ; ^&dagger ; ; Eun-Sook Park¹ ; ² ; ^&dagger ; ; Doo Hyun Kim¹ ; Sung Hyun Ahn¹ ; Seung Hwa Park³ ; Ah Ram Lee¹ ; Soree Park¹ ; Hong Seok Kang¹ ; Ji-Hyun Lee⁴ ; Jong Man Kim⁵ ; Suk-Koo Lee⁵ ; Keo-Heun Lim¹ ; Nathalie Isorce⁶ ; Shuping Tong⁷ ; Fabien Zoulim⁶ ; Kyun-Hwan Kim¹ ; ² ; ⁸ ; ^{khkim10@kku.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HBV ; hepatitis B virus ; HCC ; hepatocellular carcinoma ; CTLs ; cytotoxic T lymphocytes ; IFN-γ ; interferon-gamma ; TNF-α ; tumor necrosis factor-alpha ; c-FLIP ; cellular FLICE-inhibitory protein ; DEDs ; death effector domains ; DISC ; death-inducing signaling complex ; HSV-1 ; herpes simplex virus type 1 ; iDCs ; in immature dendritic cells ; HPV ; human papillomavirus ; siRNA ; small interfering RNA ; CHB ; chronic hepatitis B ; LMV ; lamivudine ; FADD ; Fas-associated death domain ; IP ; immunoprecipitation ; SSZ ; sulf
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：268-277
• 全文大小：2232 K

文摘

Cytokines are key molecules implicated in the defense against virus infection. Tumor necrosis factor-alpha (TNF-α) is well known to block the replication of hepatitis B virus (HBV). However, the molecular mechanism and the downstream effector molecules remain largely unknown.

Methods

In this study, we investigated the antiviral effect and mechanism of p22-FLIP (FLICE-inhibitory protein) by ectopic expression in vitro and in vivo. In addition, to provide the biological relevance of our study, we examined that the p22-FLIP is involved in TNF-α-mediated suppression of HBV in primary human hepatocytes.

Results

We found that p22-FLIP, a newly discovered c-FLIP cleavage product, inhibited HBV replication at the transcriptional level in both hepatoma cells and primary human hepatocytes, and that c-FLIP conversion to p22-FLIP was stimulated by the TNF-α/NF-κB pathway. p22-FLIP inhibited HBV replication through the upregulation of HNF3β but downregulation of HNF4α, thus inhibiting both HBV enhancer elements. Finally, p22-FLIP potently inhibited HBV DNA replication in a mouse model of HBV replication.

Conclusions

Taken together, these findings suggest that the anti-apoptotic p22-FLIP serves a novel function of inhibiting HBV transcription, and mediates the antiviral effect of TNF-α against HBV replication.