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Open AccessArticle

The Combination of IFN β and TNF Induces an Antiviral and Immunoregulatory Program via Non-Canonical Pathways Involving STAT2 and IRF9

1
CRCHUM—Centre Hospitalier de l’Université de Montréal, Montréal, QC H2X 0A9, Canada
2
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
3
Centre Robert Cedergren en Bioinformatique et Génomique, Université de Montréal, Montréal, QC H3T 1J4, Canada
4
Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada
5
Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
*
Author to whom correspondence should be addressed.
Cells 2019, 8(8), 919; https://doi.org/10.3390/cells8080919
Received: 17 July 2019 / Revised: 12 August 2019 / Accepted: 14 August 2019 / Published: 17 August 2019
(This article belongs to the Special Issue Cell Biology of Viral Infections)
Interferon (IFN) β and Tumor Necrosis Factor (TNF) are key players in immunity against viruses. Compelling evidence has shown that the antiviral and inflammatory transcriptional response induced by IFNβ is reprogrammed by crosstalk with TNF. IFNβ mainly induces interferon-stimulated genes by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway involving the canonical ISGF3 transcriptional complex, composed of STAT1, STAT2, and IRF9. The signaling pathways engaged downstream of the combination of IFNβ and TNF remain elusive, but previous observations suggested the existence of a response independent of STAT1. Here, using genome-wide transcriptional analysis by RNASeq, we observed a broad antiviral and immunoregulatory response initiated in the absence of STAT1 upon IFNβ and TNF costimulation. Additional stratification of this transcriptional response revealed that STAT2 and IRF9 mediate the expression of a wide spectrum of genes. While a subset of genes was regulated by the concerted action of STAT2 and IRF9, other gene sets were independently regulated by STAT2 or IRF9. Collectively, our data supports a model in which STAT2 and IRF9 act through non-canonical parallel pathways to regulate distinct pool of antiviral and immunoregulatory genes in conditions with elevated levels of both IFNβ and TNF. View Full-Text
Keywords: interferon; tumor necrosis factor; STAT; interferon regulatory factor; antiviral; autoimmunity; inflammation interferon; tumor necrosis factor; STAT; interferon regulatory factor; antiviral; autoimmunity; inflammation
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Mariani, M.K.; Dasmeh, P.; Fortin, A.; Caron, E.; Kalamujic, M.; Harrison, A.N.; Hotea, D.I.; Kasumba, D.M.; Cervantes-Ortiz, S.L.; Mukawera, E.; Serohijos, A.W.R.; Grandvaux, N. The Combination of IFN β and TNF Induces an Antiviral and Immunoregulatory Program via Non-Canonical Pathways Involving STAT2 and IRF9. Cells 2019, 8, 919.

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