PMID- 26409214
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20220330
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 64
IP  - 2
DP  - 2016 Feb
TI  - Cleaved c-FLIP mediates the antiviral effect of TNF-alpha against hepatitis B virus 
      by dysregulating hepatocyte nuclear factors.
PG  - 268-277
LID - S0168-8278(15)00630-3 [pii]
LID - 10.1016/j.jhep.2015.09.012 [doi]
AB  - BACKGROUND & AIMS: Cytokines are key molecules implicated in the defense against 
      virus infection. Tumor necrosis factor-alpha (TNF-alpha) 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-alpha-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-alpha/NF-kappaB pathway. p22-FLIP inhibited HBV replication through the upregulation 
      of HNF3beta but downregulation of HNF4alpha, 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-alpha against HBV replication.
CI  - Copyright (c) 2015 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Park, Yong Kwang
AU  - Park YK
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea; KU Open 
      Innovation Center, Konkuk University, Seoul, Republic of Korea.
FAU - Park, Eun-Sook
AU  - Park ES
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea; KU Open 
      Innovation Center, Konkuk University, Seoul, Republic of Korea.
FAU - Kim, Doo Hyun
AU  - Kim DH
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
FAU - Ahn, Sung Hyun
AU  - Ahn SH
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
FAU - Park, Seung Hwa
AU  - Park SH
AD  - Department of Anatomy, School of Medicine, Konkuk University, Seoul, Republic of 
      Korea.
FAU - Lee, Ah Ram
AU  - Lee AR
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
FAU - Park, Soree
AU  - Park S
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
FAU - Kang, Hong Seok
AU  - Kang HS
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
FAU - Lee, Ji-Hyun
AU  - Lee JH
AD  - Samsung Biomedical Research Institute, Seoul, Republic of Korea.
FAU - Kim, Jong Man
AU  - Kim JM
AD  - Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of 
      Medicine, Seoul, Republic of Korea.
FAU - Lee, Suk-Koo
AU  - Lee SK
AD  - Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of 
      Medicine, Seoul, Republic of Korea.
FAU - Lim, Keo-Heun
AU  - Lim KH
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
FAU - Isorce, Nathalie
AU  - Isorce N
AD  - INSERM Unite 1052, Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon 
      University, Lyon, France.
FAU - Tong, Shuping
AU  - Tong S
AD  - Liver Research Center, Rhode Island Hospital, Brown University, Providence, RI, 
      USA.
FAU - Zoulim, Fabien
AU  - Zoulim F
AD  - INSERM Unite 1052, Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon 
      University, Lyon, France.
FAU - Kim, Kyun-Hwan
AU  - Kim KH
AD  - Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, 
      IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea; KU Open 
      Innovation Center, Konkuk University, Seoul, Republic of Korea; Research 
      Institute of Medical Sciences, Konkuk University, Seoul, Republic of Korea. 
      Electronic address: khkim10@kku.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150925
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Antiviral Agents)
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (DNA, Viral)
RN  - 0 (Hepatocyte Nuclear Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/pharmacology
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein/*metabolism
MH  - Cell Line
MH  - DNA, Viral/metabolism
MH  - *Hepatitis B virus/drug effects/physiology
MH  - Hepatocyte Nuclear Factors/metabolism
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Mice
MH  - Models, Animal
MH  - Signal Transduction/drug effects
MH  - *Tumor Necrosis Factor-alpha/metabolism/pharmacology
MH  - Virus Replication/*drug effects
OTO - NOTNLM
OT  - HBV replication
OT  - Hepatitis B virus
OT  - TNF-alpha
OT  - p22-FLIP
EDAT- 2015/09/27 06:00
MHDA- 2016/12/15 06:00
CRDT- 2015/09/27 06:00
PHST- 2015/07/06 00:00 [received]
PHST- 2015/08/31 00:00 [revised]
PHST- 2015/09/14 00:00 [accepted]
PHST- 2015/09/27 06:00 [entrez]
PHST- 2015/09/27 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - S0168-8278(15)00630-3 [pii]
AID - 10.1016/j.jhep.2015.09.012 [doi]
PST - ppublish
SO  - J Hepatol. 2016 Feb;64(2):268-277. doi: 10.1016/j.jhep.2015.09.012. Epub 2015 Sep 
      25.