Abstract
BackgroundThe pro-inflammatory cytokine interferon gamma (IFNγ), a key player in various neurological diseases, was recently shown to induce a dysregulated phenotype in neural stem/precursor cells (NSPCs) that is characterized by the simultaneous expression of glial and neuronal markers and irregular electrophysiological properties. Thus far, the mechanisms of this phenomenon have remained unclear.Methodology/Principal FindingsTo determine if binding of the signal transducers and activators of transcription (Stat 1) to the sonic hedgehog (SHH) promoter is important for this phenomenon to occur, chromatin immunoprecipitation and pharmacological inhibition studies were performed. We report here that the activation of both the Stat 1 and SHH pathways is necessary to elicit the dysregulated phenotype.Conclusions/SignificanceThus, blocking these pathways might preserve functional differentiation of NSPCs under inflammatory conditions leading to more effective regeneration.
Highlights
The pro-inflammatory cytokine IFNc is mainly produced by cytotoxic CD8+ T-cells, natural killer cells [1], astrocytes, fibroblasts and endothelial cells [2,3,4] under normal or pathological conditions after stroke, cerebral traumata or in the course of inflammatory brain diseases [5]
Genotypic and Phenotypic Dysregulation of neural stem/precursor cells (NSPCs) and Effects of sonic hedgehog (SHH) Antagonism To verify if SHH signaling is involved in generating the IFNcinduced phenotype in NSPCs, we antagonized SHH signaling with cyclopamine during IFNc exposure
In a first set of experiments, we verified the induction of the dysregulated glial fibrillaric acid protein (GFAP)+/bIII-tubulin+ phenotype by IFNc treatment of NSPCs under the influence of growth factors
Summary
The pro-inflammatory cytokine IFNc is mainly produced by cytotoxic CD8+ T-cells, natural killer cells [1], astrocytes, fibroblasts and endothelial cells [2,3,4] under normal or pathological conditions after stroke, cerebral traumata or in the course of inflammatory brain diseases [5]. IFNc affects murine NSPCs in vitro leading to a dysregulated phenotype [6]. This phenotype is characterized by reduced proliferative activity and a synchronous up-regulation of mature neuronal and glial markers in the presence of growth factors. The IFNcinduced phenotype bears electrophysiological properties that are indiscernible from undifferentiated NSPCs. The mechanisms involved in IFNc-induced NSPC dysregulation are unknown. The pro-inflammatory cytokine interferon gamma (IFNc), a key player in various neurological diseases, was recently shown to induce a dysregulated phenotype in neural stem/precursor cells (NSPCs) that is characterized by the simultaneous expression of glial and neuronal markers and irregular electrophysiological properties. The mechanisms of this phenomenon have remained unclear
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