Interferon-γ Promotes Differentiation of Neural Progenitor Cells via the JNK Pathway

Kim, So Jung; Son, Tae Gen; Kim, Keun-Ho; Park, Hee Ra; Mattson, Mark P.; Lee, Joo Young

doi:10.1007/s11064-007-9323-z

Cited by 77 publications

(83 citation statements)

References 34 publications

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“…Our results reveal that IFN␥ deficiency leads to increased neuronal production in vitro, with IFN␥ treatment of wild-type cells producing the opposite effect. In contrast, IFN␥ has been reported previously to promote neuronal differentiation of NPs (Wong et al, 2004;Kim et al, 2007;Leipzig et al, 2010), possibly as a result of different assay conditions (e.g., Wong et al exposed dissociated neurosphere cells to IFN␥ throughout differentiation, whereas in our paradigm, the treated NPs differentiated in IFN␥-free medium). Importantly, our in vitro findings were strongly supported by the observation that IFN␥ deficiency results in an increased number of newborn neurons in the olfactory bulb, providing the first evidence that endogenous IFN␥ controls neuronal production.…”

Section: Discussioncontrasting

confidence: 72%

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: Discussioncontrasting

confidence: 72%

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

Li¹,

Walker²,

Zhang³

et al. 2010

Journal of Neuroscience

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“…[42][43][44] Although untested, there is a possibility that IFN␥ antagonizes these latter pathways or acts via a completely unrelated mechanism to suppress tau hyperphosphorylation. Signs of marked neurogenesis were also evident in IFN␥-expressing 3ϫTg-AD mice, a finding confirmed in a different murine AD model in the recent report from Baron et al 36 IFN␥ has been shown to promote neuronal differentiation in vitro, 45,46 neuronal plasticity, and receptor clustering. 47 Moreover, human neural stem/progenitor cell cultures express the cognate receptors for IFN␥, termed IFN-␥-R␣ and IFN-␥-R␤, and are driven toward a neuronal fate when cultured in the presence of IFN␥.…”

Section: Brdu Incorporationsupporting

confidence: 63%

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

Mastrangelo

Sudol

Narrow

et al. 2009

The American Journal of Pathology

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Inflammatory processes, including the episodic and/ or chronic elaboration of cytokines , have been identified as playing key roles in a number of neurological disorders. Whether these activities impart a disease-resolving and/or contributory outcome depends at least in part on the disease context, stage of pathogenesis, and cellular milieu in which these factors are released. Interferon-␥ (IFN␥) is one such cytokine that produces pleiotropic effects in the brain. It is protective by ensuring maintenance of virus latency after infection, yet deleterious by recruiting and activating microglia that secrete potentially damaging factors at sites of brain injury. Using the triple-transgenic mouse model of Alzheimer's disease (3؋Tg-AD), which develops amyloid and tau pathologies in a pattern reminiscent of human Alzheimer's disease, we initiated chronic intrahippocampal expression of IFN␥ through delivery of a serotype-1 recombinant adeno-associated virus vector (rAAV1-IFN␥). Ten months of IFN␥ expression led to an increase in microglial activation, steady-state levels of proinflammatory cytokine and chemokine transcripts, and severity of amyloid-related pathology. In contrast, these rAAV1-IFN␥-treated 3؋Tg-AD mice also exhibited diminished phospho-tau pathology and evidence of increased neurogenesis. Overall, IFN␥ mediates what seem to be diametrically opposed functions in the setting of AD-related neurodegeneration. Gaining an understanding as to how these apparently divergent functions are interrelated and controlled could elucidate new therapeutic strategies designed to harness the neuroprotective activity of IFN␥. (Am J Pathol

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“…IFNγ increases p11 through a direct interaction with IFNγ binding sites on the p11 promoter (22). IFNγ increases neurite outgrowth (23), promotes neuronal differentiation (24), and enhances neurogenesis (25), all of which are consistent with antidepressant-like activity (26). However, it has been suggested that IFNγ mediates depression-behaviors caused by immune activation (27).…”

Section: Discussionmentioning

confidence: 99%

Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

Warner-Schmidt

Vanover

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

244

209

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Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A “cytokine hypothesis” of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, “sequenced treatment alternatives to relieve depression” (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.

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Interferon-γ Promotes Differentiation of Neural Progenitor Cells via the JNK Pathway

Cited by 77 publications

References 34 publications

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

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

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

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