title: Cleaved c-FLIP mediates the antiviral effect of TNF-α against hepatitis B virus by dysregulating hepatocyte nuclear factors.
abstract: OBJECTIVE
  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.affiliation: 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.
authors.forename: Yong Kwang
authors.initials: YK
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Anatomy, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Seung Hwa
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Ah Ram
authors.initials: AR
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Soree
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Kang
authors.affiliation: Samsung Biomedical Research Institute, Seoul, Republic of Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jong Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Suk-Koo
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Keo-Heun
authors.initials: KH
authors.lastname: Lim
authors.affiliation: INSERM Unité 1052, Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Isorce
authors.affiliation: Liver Research Center, Rhode Island Hospital, Brown University, Providence, RI, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Tong
authors.affiliation: INSERM Unité 1052, Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: 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.
authors.forename: Kyun-Hwan
authors.initials: KH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology; D051536:Hepatocyte Nuclear Factors / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D023421:Models, Animal; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D004279:DNA, Viral; D051536:Hepatocyte Nuclear Factors; D014409:Tumor Necrosis Factor-alpha
keywords: HBV replication; Hepatitis B virus; TNF-α; p22-FLIP