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

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

SUBMITTER: Wang W 

PROVIDER: S-EPMC4858707 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other