IFN-α has been used for decades to treat chronic hepatitis B and C, and as an off-label treatment for 

Brandsma, J.H. (Johan)

Fuhler, G.M. (Gwenny)

Hakim, M.S. (Mohamad)

Laan, L.J.W. (Luc) van der

Metselaar, H.J. (Herold)

Pan, Q. (Qiuwei)

Peppelenbosch, M.P. (Maikel)

Poot, R.A. (Raymond)

Smits, M.J.M. (Ron)

Sprengers, D. (Dave)

Wang, W. (Wenshi)

Wang, Y. (Yijin)

Woude, C.J. (Janneke) van der

Xu, L. (Lei)

Yin, Y. (Yuebang)

Zhou, X. (Xinying)

PubMed

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-κ B 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

Erasmus University Digital Repository

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

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

Wang, Wenshi

Xu, L (Lei)

Brandsma, Johan

Wang, Yongyi

Hakim, MS (Mohamad)

Zhou, XY

Yin, YB (Yuebang)

Fuhler, Gwenny

van der Laan, Luc

van der Woude, C.J.

Sprengers, Dave

Metselaar, Herold

Smits, Ron

Poot, Raymond

Peppelenbosch, Maikel

Pan, Qiuwei

EUR Research Repository

English

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

https://pure.eur.nl/ws/files/47690679/REPUB_88275-OA.pdf

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

Abstract

Similar works

Full text

Available Versions

Erasmus University Digital Repository

EUR Research Repository

EUR Research Repository