title: Type I interferon-regulated gene expression and signaling in murine mixed glial cells lacking signal transducers and activators of transcription 1 or 2 or interferon regulatory factor 9.
abstract: Type I interferons (IFN-I) are critical in antimicrobial and antitumor defense. Although IFN-I signal via the interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2, and IRF9, IFN-I can mediate significant biological effects via ISGF3-independent pathways. For example, the absence of STAT1, STAT2, or IRF9 exacerbates neurological disease in transgenic mice with CNS production of IFN-I. Here we determined the role of IFN-I-driven, ISGF3-independent signaling in regulating global gene expression in STAT1-, STAT2-, or IRF9-deficient murine mixed glial cell cultures (MGCs). Compared with WT, the expression of IFN-α-stimulated genes (ISGs) was reduced in number and magnitude in MGCs that lacked STAT1, STAT2, or IRF9. There were significantly fewer ISGs in the absence of STAT1 or STAT2versusin the absence of IRF9. The majority of ISGs regulated in the STAT1-, STAT2-, or IRF9-deficient MGCs individually were shared with WT. However, only a minor number of ISGs were common to WT and STAT1-, STAT2-, and IRF9-deficient MGCs. Whereas signal pathway activation in response to IFN-α was rapid and transient in WT MGCs, this was delayed and prolonged and correlated with increased numbers of ISGs expressed at 12 hversus4 h of IFN-α exposure in all three IFN-I signaling-deficient MGCs. In conclusion, 1) IFN-I can mediate ISG expression in MGCs via ISGF3-independent signaling pathways but with reduced efficiency, with delayed and prolonged kinetics, and is more dependent on STAT1 and STAT2 than IRF9; and 2) signaling pathways not involving STAT1, STAT2, or IRF9 play a minor role only in mediating ISG expression in MGCs.
authors.affiliation: From the School of Molecular Bioscience.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: From the School of Molecular Bioscience.|Bosch Institute, and.|Charles Perkins Centre, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Markus J
authors.identifier: 0000-0001-5111-3978
authors.initials: MJ
authors.lastname: Hofer
authors.affiliation: From the School of Molecular Bioscience.
authors.forename: Pattama
authors.initials: P
authors.lastname: Songkhunawej
authors.affiliation: From the School of Molecular Bioscience.
authors.forename: So Ri
authors.initials: SR
authors.lastname: Jung
authors.affiliation: From the School of Molecular Bioscience.
authors.forename: Dale
authors.initials: D
authors.lastname: Hancock
authors.affiliation: From the School of Molecular Bioscience.
authors.forename: Gareth
authors.initials: G
authors.lastname: Denyer
authors.affiliation: From the School of Molecular Bioscience, iain.campbell@sydney.edu.au.|Bosch Institute, and.|Charles Perkins Centre, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Iain L
authors.identifier: 0000-0001-8681-1100
authors.initials: IL
authors.lastname: Campbell
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D050832:Interferon-Stimulated Gene Factor 3 / Q000235:genetics / Q000378:metabolism; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494228:Isgf3g protein, mouse
keywords: gene expression; glial cell; interferon; interferon regulatory factor (IRF); signal transducers and activators of transcription 1 (STAT1)