title: Convergent Transcription of Interferon-stimulated Genes by TNF-α and IFN-α Augments Antiviral Activity against HCV and HEV.
abstract: IFN-α has been used for decades to treat chronic hepatitis B and C, and as an off-label treatment for some cases of hepatitis E virus (HEV) infection. TNF-α is another important cytokine involved in inflammatory disease, which can interact with interferon signaling. Because interferon-stimulated genes (ISGs) are the ultimate antiviral effectors of the interferon signaling, this study aimed to understand the regulation of ISG transcription and the antiviral activity by IFN-α and TNF-α. In this study, treatment of TNF-α inhibited replication of HCV by 71 ± 2.4% and HEV by 41 ± 4.9%. Interestingly, TNF-α induced the expression of a panel of antiviral ISGs (2-11 fold). Blocking the TNF-α signaling by Humira abrogated ISG induction and its antiviral activity. Chip-seq data analysis and mutagenesis assay further revealed that the NF-κB protein complex, a key downstream element of TNF-α signaling, directly binds to the ISRE motif in the ISG promoters and thereby drives their transcription. This process is independent of interferons and JAK-STAT cascade. Importantly, when combined with IFN-α, TNF-α works cooperatively on ISG induction, explaining their additive antiviral effects. Thus, our study reveals a novel mechanism of convergent transcription of ISGs by TNF-α and IFN-α, which augments their antiviral activity against HCV and HEV.
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, Medical Genetics Cluster, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Brandsma
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.|Department of Microbiology, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Mohamad S
authors.initials: MS
authors.lastname: Hakim
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Yuebang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Gwenny M
authors.initials: GM
authors.lastname: Fuhler
authors.affiliation: Department of Surgery, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: C Janneke
authors.initials: CJ
authors.lastname: van der Woude
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.affiliation: Department of Cell Biology, Medical Genetics Cluster, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Poot
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Postgraduate School Molecular Medicine, Erasmus MC-University Medical Center, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D016752:Hepatitis E virus / Q000276:immunology* / Q000502:physiology; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha