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

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 Jan...

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Published in:	Cells (Basel, Switzerland) Vol. 8; no. 8; p. 919
Main Authors:	Mariani, Mélissa K, Dasmeh, Pouria, Fortin, Audray, Caron, Elise, Kalamujic, Mario, Harrison, Alexander N, Hotea, Diana I, Kasumba, Dacquin M, Cervantes-Ortiz, Sandra L, Mukawera, Espérance, Serohijos, Adrian W R, Grandvaux, Nathalie
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 17-08-2019 MDPI
Subjects:	A549 Cells Antibodies antiviral autoimmunity Binding sites Cytokines Gene expression Genomes Humans Immunoregulation Inflammation interferon interferon regulatory factor Interferon-beta - physiology Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism Janus kinase Kinases Laboratories Life sciences STAT Stat1 protein Stat2 protein STAT2 Transcription Factor - metabolism Transcription Tumor necrosis factor Tumor Necrosis Factor-alpha - physiology Tumor necrosis factor-TNF Vesicular Stomatitis - immunology Vesicular stomatitis Indiana virus - immunology β-Interferon Canada United States > US STAT autoimmunity tumor necrosis factor inflammation antiviral interferon regulatory factor interferon
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2073-4409 2073-4409
DOI:	10.3390/cells8080919