Yong Kwang Park1, 2, a, Eun-Sook Park1, 2, a, 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,*
1 Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
2 KU Open Innovation Center, Konkuk University, Seoul, Korea
3 Department of Anatomy, School of Medicine, Konkuk University, Seoul, Korea
4 Samsung Biomedical Research Institute, Seoul, Korea
5 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
6 INSERM Unite 1052, Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
7 Liver Research Center, Rhode Island Hospital, Brown University, Providence, Rhode Island, USA
8 Research Institute of Medical Sciences, Konkuk University, Seoul, Korea
a These authors contributed equally to this work.
*Corresponding author.
Abstract
Background & Aims
Cytokines are key molecules implicated in defense against virus infection. 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 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 up-regulation of HNF3β but down-regulation of HNF4α, thus inhibiting both HBV enhancer elements. Finally, p 22-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.
Keywords : Hepatitis B virus; TNF-α; p22-FLIP; HBV replication