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

Abstract

BACKGROUND & AIMS:

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.

• Authors: Yong Kwang Park, Eun-Sook Park, Doo Hyun Kim, Sung Hyun Ahn, Seung Hwa Park, Ah Ram Lee, Soree Park, Hong Seok Kang, Ji-Hyun Lee, Jong Man Kim, Suk-Koo Lee, Keo-Heun Lim, Nathalie Isorce, Shuping Tong, Fabien Zoulim, Kyun-Hwan Kim
• Journal: Journal of hepatology (J Hepatol) Vol. 64 Issue 2 Pg. 268-277 (Feb 2016) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 26409214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• CASP8 and FADD-Like Apoptosis Regulating Protein
• DNA, Viral
• Hepatocyte Nuclear Factors
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antiviral Agents (pharmacology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Cell Line
• DNA, Viral (metabolism)
• Hepatitis B virus (drug effects, physiology)
• Hepatocyte Nuclear Factors (metabolism)
• Hepatocytes (metabolism)
• Humans
• Mice
• Models, Animal
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)
• Virus Replication (drug effects)