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IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity.

Pereira L, Font-Nieves M, Van den Haute C, Baekelandt V, Planas AM, Pozas E - Front Cell Neurosci (2015)

Bottom Line: We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3.The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels.Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Unit of Brain Ischemia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona Spain ; Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona Spain.

ABSTRACT
The adult subventricular zone (SVZ) contains Nestin+ progenitors that differentiate mainly into neuroblasts. Our previous data showed that interleukin-10 (IL-10) regulates SVZ adult neurogenesis by up-regulating the expression of pro-neural genes and modulating cell cycle exit. Here we addressed the specific mechanism through which IL-10 carries out its signaling on SVZ progenitors. We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3. The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels. Silencing STAT3 expression by lentiviral vectors also impaired neurogenesis by blocking the effects of IL-10. Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

No MeSH data available.


Related in: MedlinePlus

In vivo IL-10 induces the phosphorylation of ERK and STAT3. (A) Phosphorylation of ERK1/2 and STAT3ser727 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an ICV injection of IL-10 (1 ul of 50 ηgr/ml; n = 3). (B) Pictures of dorsal SVZ after ICV IL-10 injection. ERK1/2 phosphorylation (green) takes place rapidly (30 min) in Nestin+ (red) and Mash1+ (red) progenitors cells in dorsal SVZ after in vivo IL-10 stimulation. To-pro (blue) stained all nuclei (n = 3). Scale bar, 30 μm.
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Figure 3: In vivo IL-10 induces the phosphorylation of ERK and STAT3. (A) Phosphorylation of ERK1/2 and STAT3ser727 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an ICV injection of IL-10 (1 ul of 50 ηgr/ml; n = 3). (B) Pictures of dorsal SVZ after ICV IL-10 injection. ERK1/2 phosphorylation (green) takes place rapidly (30 min) in Nestin+ (red) and Mash1+ (red) progenitors cells in dorsal SVZ after in vivo IL-10 stimulation. To-pro (blue) stained all nuclei (n = 3). Scale bar, 30 μm.

Mentions: Notch regulates cell survival in NSC cells by means of JAK-independent activation of STAT3 through AKT and mTOR phosphorylation (Androutsellis-Theotokis et al., 2006). In cell carcinomas, IL receptors activate STAT3 phosphorylation by JAK and/or MAPKs (Lee et al., 2006). Stimulation assays with IL-10 in SVZ cell cultures showed a rapid and strong induction of ERK1/2 phosphorylation (Figure 2A). pERK1/2 was present only in a small number of Nestin+ cells in the experimental control, as shown by double-immunofluorescence analysis. The acute presence of IL-10 induced a robust increase in the number of Nestin+ cells showing ERK1/2 phosphorylation (Figures 2B,C). The stimulation of ERK1/2 phosphorylation was restricted to Nestin+ progenitors and pERK1/2 was not detected in Nestin negative cells. We conclude that IL-10 targets specifically Nestin+ progenitors, in which promotes ERK1/2 activation. In contrast, AKT phosphorylation was not affected by the treatment with the cytokine (data not shown). The same situation was observed in vivo after acute treatment of adult mice with IL-10. A single ICV administration of IL-10 into the LV of the mice induced ERK1/2 and pSTAT3ser727 phosphorylation in the SVZ niche of both hemispheres, ctr and ipsilateral to the injection site (Figure 3A). Further studies on SVZ histological sections by double immunofluorescences revealed that IL-10 induced rapid pERK1/2 activation in Nestin+ progenitors and Mash1+ (TAPs) cells (Figure 3B). We were unable to assess the presence of pSTAT3ser727in vivo since the antibodies available did not work on brain sections.


IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity.

Pereira L, Font-Nieves M, Van den Haute C, Baekelandt V, Planas AM, Pozas E - Front Cell Neurosci (2015)

In vivo IL-10 induces the phosphorylation of ERK and STAT3. (A) Phosphorylation of ERK1/2 and STAT3ser727 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an ICV injection of IL-10 (1 ul of 50 ηgr/ml; n = 3). (B) Pictures of dorsal SVZ after ICV IL-10 injection. ERK1/2 phosphorylation (green) takes place rapidly (30 min) in Nestin+ (red) and Mash1+ (red) progenitors cells in dorsal SVZ after in vivo IL-10 stimulation. To-pro (blue) stained all nuclei (n = 3). Scale bar, 30 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: In vivo IL-10 induces the phosphorylation of ERK and STAT3. (A) Phosphorylation of ERK1/2 and STAT3ser727 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an ICV injection of IL-10 (1 ul of 50 ηgr/ml; n = 3). (B) Pictures of dorsal SVZ after ICV IL-10 injection. ERK1/2 phosphorylation (green) takes place rapidly (30 min) in Nestin+ (red) and Mash1+ (red) progenitors cells in dorsal SVZ after in vivo IL-10 stimulation. To-pro (blue) stained all nuclei (n = 3). Scale bar, 30 μm.
Mentions: Notch regulates cell survival in NSC cells by means of JAK-independent activation of STAT3 through AKT and mTOR phosphorylation (Androutsellis-Theotokis et al., 2006). In cell carcinomas, IL receptors activate STAT3 phosphorylation by JAK and/or MAPKs (Lee et al., 2006). Stimulation assays with IL-10 in SVZ cell cultures showed a rapid and strong induction of ERK1/2 phosphorylation (Figure 2A). pERK1/2 was present only in a small number of Nestin+ cells in the experimental control, as shown by double-immunofluorescence analysis. The acute presence of IL-10 induced a robust increase in the number of Nestin+ cells showing ERK1/2 phosphorylation (Figures 2B,C). The stimulation of ERK1/2 phosphorylation was restricted to Nestin+ progenitors and pERK1/2 was not detected in Nestin negative cells. We conclude that IL-10 targets specifically Nestin+ progenitors, in which promotes ERK1/2 activation. In contrast, AKT phosphorylation was not affected by the treatment with the cytokine (data not shown). The same situation was observed in vivo after acute treatment of adult mice with IL-10. A single ICV administration of IL-10 into the LV of the mice induced ERK1/2 and pSTAT3ser727 phosphorylation in the SVZ niche of both hemispheres, ctr and ipsilateral to the injection site (Figure 3A). Further studies on SVZ histological sections by double immunofluorescences revealed that IL-10 induced rapid pERK1/2 activation in Nestin+ progenitors and Mash1+ (TAPs) cells (Figure 3B). We were unable to assess the presence of pSTAT3ser727in vivo since the antibodies available did not work on brain sections.

Bottom Line: We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3.The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels.Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Unit of Brain Ischemia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona Spain ; Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona Spain.

ABSTRACT
The adult subventricular zone (SVZ) contains Nestin+ progenitors that differentiate mainly into neuroblasts. Our previous data showed that interleukin-10 (IL-10) regulates SVZ adult neurogenesis by up-regulating the expression of pro-neural genes and modulating cell cycle exit. Here we addressed the specific mechanism through which IL-10 carries out its signaling on SVZ progenitors. We found that, in vitro and in vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3. The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels. Silencing STAT3 expression by lentiviral vectors also impaired neurogenesis by blocking the effects of IL-10. Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis.

No MeSH data available.


Related in: MedlinePlus