Convergent Transcription of Interferon-stimulated Genes by TNF-alpha and IFN-alpha Augments Antiviral Activity against HCV and HEV

Wenshi Wang, L (Lei) Xu, Johan Brandsma, Yongyi Wang, MS (Mohamad) Hakim, XY Zhou, YB (Yuebang) Yin, Gwenny Fuhler, Luc van der Laan, C.J. van der Woude, Dave Sprengers, Herold Metselaar, Ron Smits, Raymond Poot, Maikel Peppelenbosch, Qiuwei Pan

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Abstract

IFN-alpha 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-alpha 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-alpha and TNF-alpha. In this study, treatment of TNF-alpha inhibited replication of HCV by 71 +/- 2.4% and HEV by 41 +/- 4.9%. Interestingly, TNF-alpha induced the expression of a panel of antiviral ISGs (2-11 fold). Blocking the TNF-alpha signaling by Humira abrogated ISG induction and its antiviral activity. Chip-seq data analysis and mutagenesis assay further revealed that the NF-kappa B protein complex, a key downstream element of TNF-alpha 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-alpha, TNF-alpha works cooperatively on ISG induction, explaining their additive antiviral effects. Thus, our study reveals a novel mechanism of convergent transcription of ISGs by TNF-alpha and IFN-alpha, which augments their antiviral activity against HCV and HEV.
Original languageUndefined/Unknown
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016

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