title: The antiviral cytokine interferon-gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation.
abstract: Neural stem/progenitor cells (NPSCs) express receptors for many inflammatory cytokines, with varying effects on differentiation and proliferation depending on the stage of development and the milieu of inflammatory mediators. In primary neurons and astrocytes, we recently showed that interferon gamma (IFNγ), a potent antiviral cytokine that is required for the control and clearance of many central nervous system (CNS) infections, could differentially affect cell survival and cell cycle progression depending upon the cell type and the profile of activated intracellular signaling molecules. Here, we show that IFNγ inhibits proliferation of primary NSPCs through dephosphorylation of the tumor suppressor Retinoblastoma protein (pRb), which is dependent on activation of signal transducers and activators of transcription-1 (STAT1) signaling pathways. Our results show i) IFNγ inhibits neurosphere growth and proliferation rate in a dose-dependent manner; ii) IFNγ blocks cell cycle progression through a late-stage G1/S phase restriction; iii) IFNγ induces phosphorylation and expression of STAT1 and STAT3; iv) IFNγ decreases cyclin E/cdk2 expression and reduces phosphorylation of cyclin D1 and pRb on serine residue 795; and v) the effects of IFNγ on NSPC proliferation, cell cycle protein expression, and pRb phosphorylation are STAT1-dependent. These data define a mechanism by which IFNγ could contribute to a reduction in NSPC proliferation in inflammatory conditions. Further delineation of the effects of inflammatory cytokines on NSPC growth could improve our understanding of how CNS infections and other inflammatory events disrupt brain development and NSPC function. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
authors.affiliation: Duquesne University, Mylan School of Pharmacy, 600 Forbes Avenue, Pittsburgh, PA, 15282.
authors.forename: Apurva
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Duquesne University, Mylan School of Pharmacy, 600 Forbes Avenue, Pittsburgh, PA, 15282.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Scully
authors.affiliation: Duquesne University, Mylan School of Pharmacy, 600 Forbes Avenue, Pittsburgh, PA, 15282.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53
chemical_list: D000998:Antiviral Agents; D016213:Cyclins; D016160:Retinoblastoma Protein; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; D016159:Tumor Suppressor Protein p53; D012694:Serine; D007371:Interferon-gamma
keywords: Interferon-gamma; cell cycle; neural stem/progenitor cell; retinoblastoma protein; stat1