The signal transduction molecule, Stat1, is critical for the expression of type I and II interferon (IFN)-responsive genes in most cells; however, we previously showed that primary hippocampal mouse neurons express low basal Stat1, with delayed and attenuated expression of IFN-responsive genes. Moreover, IFNγ-dependent resolution of a neurotropic viral challenge in permissive mice is Stat1-independent. Here, we show that exogenous INFγ has no deleterious impact on neuronal viability, and staurosporine-induced apoptosis in neurons is significantly blunted by the addition of INFγ, suggesting that INFγ confers a pro-survival signal in neurons. To identify the pathways induced by INFγ in neurons, the activation of alternative signal transducers associated with INFγ signaling was assessed. Rapid and pronounced activation of extracellular signal regulated kinase (Erk1/2) was observed in neurons, compared to a modest response in fibroblasts. Moreover, the absence of Stat1 in primary fibroblasts led to enhanced Erk activation following IFNγ addition, implying that the cell-specific availability of signal transducers can diversify the cellular response following IFN engagement.

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.

Interferon-gamma (IFNγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNγ mediates non-cytolytic viral control in infected neurons. However, IFNγ also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNγ, neural stem/progenitor cells (NSPCs), the only pluripotent cells in the developing and adult brain, are often altered during CNS insults. Recent studies highlight the complex effects of IFNγ on NSPC activity in neurodegenerative diseases. However, the mechanisms that mediate these effects, and the eventual outcomes for the host, are still being explored. Here, we review the effects of IFNγ on NSPC activity during different pathological insults. An improved understanding of the role of IFNγ would provide insight into the impact of immune responses on the progression and resolution of neurodegenerative diseases.