Inhibition of neurosphere proliferation by IFNγ but not IFNβ is coupled to neuronal differentiation

Lum, Maggie; Croze, Ed; Wagner, Conrad; McLenachan, Samuel; Mitrovic, Branislava; Turnley, Ann M.

doi:10.1016/j.jneuroim.2008.10.009

Cited by 30 publications

(36 citation statements)

References 39 publications

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“…The anti-proliferative action in these cells is mainly regulated via activation of signal transducer and activator of transcription 1 (STAT1) and downregulation of cyclin A and cyclin E expression (Kortylewski et al, 2004). A similar inhibitory mechanism may also exist for NPs, with a recent study reporting that IFN␥-induced NP growth arrest occurs in the G 1 phase of the cell cycle, being mediated via the STAT1-dependent signaling pathway (Lum et al, 2009). IFN␥-mediated inhibition of cell-cycle progression could also occur via upregulation of the cyclin-dependent kinase inhibitor p27 (Lum et al, 2009), a possibility supported by the finding that overexpression of p27 reduces the proliferation and self-renewal of SVZ cells (Li et al, 2009).…”

Section: Discussionmentioning

confidence: 83%

“…A similar inhibitory mechanism may also exist for NPs, with a recent study reporting that IFN␥-induced NP growth arrest occurs in the G 1 phase of the cell cycle, being mediated via the STAT1-dependent signaling pathway (Lum et al, 2009). IFN␥-mediated inhibition of cell-cycle progression could also occur via upregulation of the cyclin-dependent kinase inhibitor p27 (Lum et al, 2009), a possibility supported by the finding that overexpression of p27 reduces the proliferation and self-renewal of SVZ cells (Li et al, 2009). However, because it has also been reported that IFN␥ may partially regulate cell-cycle arrest via a STAT1-independent IFN␥-signaling pathway (Gough et al, 2008), such as acting through pRb or c-Myc in macrophages (Ramana et al, 2002) or CrKL in hematopoietic progenitors (Platanias et al, 1999), this remains a possibility.…”

Section: Discussionmentioning

confidence: 83%

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Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Li¹,

Walker²,

Zhang³

et al. 2010

Journal of Neuroscience

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Although a number of growth factors have been shown to be involved in neurogenesis, the role of inflammatory cytokines remains relatively unexplored in the normal brain. Here we investigated the effect of interferon gamma (IFN␥) in the regulation of neural precursor (NP) activity in both the developing and the adult mouse brain. Exogenous IFN␥ inhibited neurosphere formation from the wild-type neonatal and adult subventricular zone (SVZ). More importantly, however, these effects were mirrored in vivo, with mutant mice lacking endogenous IFN␥ displaying enhanced neurogenesis, as demonstrated by an increase in proliferative bromodeoxyuridinelabeled cells in the SVZ and an increased percentage of newborn neurons in the olfactory bulb. Furthermore, NPs isolated from IFN␥ null mice exhibited an increase in self-renewal ability and in the capacity to produce differentiated neurons and oligodendrocytes. These effects resulted from the direct action of IFN␥ on the NPs, as determined by single-cell assays and the fact that nearly all the neurospheres were derived from cells positive for major histocompatibility complex class I antigen, a downstream marker of IFN␥-mediated activation. Moreover, the inhibitory effect was ameliorated in the presence of SVZ-derived microglia, with their removal resulting in almost complete inhibition of NP proliferation. Interestingly, in contrast to the results obtained in the adult, exogenous IFN␥ treatment stimulated neurosphere formation from the embryonic brain, an effect that was mediated by sonic hedgehog. Together these findings provide the first direct evidence that IFN␥ acts as a regulator of the active NP pool in the non-inflammatory brain.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 83%

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Li¹,

Walker²,

Zhang³

et al. 2010

Journal of Neuroscience

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“…Moreover in adult's DG, neurogenesis is reported to rely on STAT3 activation [43]. Interferon β, typically used in treatment of MS, can activate STATs [13] thus implicated in controversial role in proliferation and differentiation of NPC in murine [44], because it can either inhibit [45], have no effect [44] or enhance the proliferation of the NPC [46]. Previous study on the role of JAK-STAT in glial differentiation showed that activation of ciliary neurotrophic factor (CNTF) receptor is associated with activation of JAK1, STAT1 and STAT3 and stimulating the differentiation of embryonic cortical precursor cells into astrocytes [13].…”

Section: Jak/stat Pathways Involvement In Neurogenesis/gliogenesismentioning

confidence: 99%

JAK-STAT Lodges in Multiple Sclerosis: Pathophysiology and Therapeutic Approach Overview

Hamid¹,

Isiyaku²,

Kalgo³

et al. 2017

OALib

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Multiple sclerosis (MS) is a complex inflammatory and demyelinating disease of central nervous system (CNS). The disease pathogenesis is not fully understood and no actual cure for the disease yet. The disease has genetic and environmental cause as fundamental factors which are identified for the disease pathogenesis so far. One of the characteristic features of the disease is inflammation cause due to activation of pro-inflammatory cells. Interference in signalling pathways such as JAK/STAT could result in physiological or pathological outcome in MS. Dysregulation of JAK/STAT signalling pathway is associated with chronic inflammatory process and immune disorders. In this review, considering the important role of JAK/STAT pathway in signal transduction of inflammatory process and immune responses in CNS, we describe the involvement of this signal transduction pathway in MS. Moreover, we consider the physiological and pathological involvement of JAK/STAT rout in neurogenesis/gliogenesis, cytokines production and as therapeutics target for managing MS.

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“…It is possible that none of these conclusions are mutually exclusive and other facets of the context require examination. In contrast to these contexts where Stat3 activation leads to glial differentiation, activation of Stat3 by IFNγ in NSCs results in the upregulation of p27 and neuronal maturation along with neurite outgrowth (37). The context in which this IFNγ-mediated Stat3 activation occurs is unclear.…”

Section: Stat3 Biology In the Developing And Adult Mammalian Nervous mentioning

confidence: 99%

“…The length of activation of the Stat3 signal also needs to be considered as this will contribute to the overall strength of the signal. While cytokine-mediated Stat3 interaction is quite short-lived in liver cells, it is prolonged in NSCs in response to CNTF and IFNγ, and is evident up to 24 hours after stimulation (33,37).…”

Section: Projections and Conclusionmentioning

confidence: 99%

STATus and Context within the Mammalian Nervous System

Rajan

2011

Mol Med

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Effective manipulation of human disease processes may be achieved by understanding transcriptional, posttranscriptional and epigenetic events that orchestrate cellular events. The levels of activation of specific molecules, spatial distribution and concentrations of relevant networks of signaling molecules along with the receptiveness of the chromatin to these signals are some of the parameters which dictate context. Effects elicited by the transcription factor signal transducers and activator of transcription 3 (Stat3) are discussed with respect to the context within which Stat3-mediated effects are elicited within the developing and adult mammalian nervous system. Stat3 signals are pivotal to the proliferation and differentiation of neural stem cells. They also participate in neuronal regeneration and cancers of the nervous system. An analysis of the context in which Stat3 activation occurs in these processes provides a potential predictive paradigm with which novel methods for intervention may be designed.

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Inhibition of neurosphere proliferation by IFNγ but not IFNβ is coupled to neuronal differentiation

Cited by 30 publications

References 39 publications

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

Endogenous Interferon Directly Regulates Neural Precursors in the Non-Inflammatory Brain

JAK-STAT Lodges in Multiple Sclerosis: Pathophysiology and Therapeutic Approach Overview

STATus and Context within the Mammalian Nervous System

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