Interleukin‐4 blocks thapsigargin‐induced cell death in rat rod photoreceptors: Involvement of cAMP/PKA pathway

Adão-Novaes, Juliana; Guterres, Céulem de Cássia Belem; Silva, Ana Gabriela Ledo Santos da; Campello-Costa, Paula; Linden, Rafael; Sholl‐Franco, Alfred

doi:10.1002/jnr.22026

Cited by 12 publications

(5 citation statements)

References 54 publications

(64 reference statements)

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“…IL-4Rα has been observed in the whole retina, mainly in the soma and outer segments of photoreceptor cells as well as in the outer and inner plexiform layers, with a pattern consistent with Müller cell processes [6,8]. Our data support the idea that IL-4 anti-inflammatory action is related to a decrease in GFAP retinal content, which is a marker of astrocyte and/or Müller cell activities.…”

Section: Discussionsupporting

confidence: 78%

“…Signal transduction through IL-4Rs involves 3 major pathways: JAK-STAT6, Raf-MEK-ERK and PI3K-Akt [1,3]. Several studies have pointed out the role of IL-4 in different processes of brain development such as neuronal survival [7,8], proliferation [6], differentiation [6,9], and synaptic plasticity [10]. However, the impact of an anti-inflammatory cytokine in the organization of central connections has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin 4 Leads to Sustained Phosphorylation of the STAT6 and ERK Pathways in the Retina and Disrupts Subcortical Visual Circuitry in Rodents

Goulart¹,

Menezes²,

Espírito-Santo³

et al. 2018

Neuroimmunomodulation

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Objective: Interleukin 4 (IL-4) is an anti-inflammatory cytokine related to different aspects of central nervous system development such as survival, proliferation, and differentiation, among others. Our goals were to investigate the effect of intravitreous treatment with IL-4 on the activation of downstream signaling pathways in the retina and the distribution of retinal axons within the superior colliculus (SC). Material and Methods: Lister hooded rats were submitted to an intravitreous injection of either IL-4 (5 U/µL) or PBS (vehicle) at postnatal day 10 (PND10). At PND11 or PND14, retinas were processed for Western blot or immunohistochemistry. At PND13, a group of animals received an intraocular injection of an anterograde tracer in the left (untreated) eye in order to label the uncrossed retinotectal axons. Results: Our data revealed that intravitreous treatment with IL-4 at PND10 leads to a decrease in GFAP content and a sustained increase in the phosphorylation of STAT6 and ERK levels in the retina. IL-4 also increases retinal axonal arbors within the SC, compared to control groups. Conclusions: These data suggest that a single in vivo treatment with IL-4 during the early stages of development modulates signaling pathways in the retina, resulting in altered binocular subcortical visual connectivity.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Interleukin 4 Leads to Sustained Phosphorylation of the STAT6 and ERK Pathways in the Retina and Disrupts Subcortical Visual Circuitry in Rodents

Goulart¹,

Menezes²,

Espírito-Santo³

et al. 2018

Neuroimmunomodulation

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“…It appears that PKA-mediated survival pathway is not limited to neurons. Cell death in rat rod photoreceptor can be blocked by interleukin-4 in a PKA dependent manner [48]. Hence it is tempting to speculate that a stimulus or reagent which can induce PKA pathway may serve as a neuroprotective reagents by reducing iron-catalyzed oxidative stress via a suppression of Dexras1.…”

Section: Discussionmentioning

confidence: 99%

PKA‐mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S‐nitrosylation

et al. 2015

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Dexras1 is a small GTPase and plays a central role in neuronal iron trafficking. We have shown that stimulation of glutamate receptors activates neuronal nitric oxide synthase, leading to S-nitrosylation of Dexras1 and a physiological increase in iron uptake. Here we report that Dexras1 is phosphorylated by PKA on serine 253, leading to a suppression of iron influx. These effects were directly associated with the levels of S-nitrosylated Dexras1, whereby PKA activation reduced Dexras1 S-nitrosylation in a dose dependent manner. Moreover, we found that adiponectin modulates Dexras1 via PKA. Hence these findings suggest the involvement of the PKA pathway in modulating glutamate-mediated ROS in neurons, and hint to a functional crosstalk between S-nitrosylation and phosphorylation.

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“…These studies suggest that the IL‐4‐induced activation of the JAK‐2 / Fyn kinase signaling pathway may contribute to the Tyr1472 phosphorylation of NR2B. Regarding the possibility of IL‐4‐induced inactivation of STEP, one potential mechanism is that IL‐4 induces accumulation of cAMP (60), which activates protein kinase A (PKA) and subsequently phosphorylates and inactivates STEP (61). We examined whether IL‐4 enhances PKA activation in primary mouse neurons using PKA substrate antibody blotting, which detects all the phosphorylated substrates of PKA, and saw no changes (unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

CNS expression of anti‐inflammatory cytokine interleukin‐4 attenuates Alzheimer's disease‐like pathogenesis in APP+PS1 bigenic mice

et al. 2010

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Cytokines play an emerging role as neurotransmitters, neuromodulators, and neurohormones in the brain. This paradigm shift in cytokine function offers a new framework to understand their roles in ameliorating neurodegenerative disorders, such as Alzheimer's disease (AD). Molecular adjuvant therapy of AD animal models with glatiramer acetate induces anti-inflammatory responses and therapeutic effects. Although these effects are potentially mediated through anti-inflammatory cytokine signaling, the exact molecular identities and pathways are poorly understood. Here, we show that virus-mediated expression of the mouse interleukin (IL)-4 gene in beta-amyloid precursor protein + presenilin-1 (APP+PS1) bigenic mice attenuates AD pathogenesis. Introduction of an adeno-associated viral (AAV) vector encoding IL-4 into the hippocampus resulted in sustained expression of IL-4, reduced astro/microgliosis, amyloid-beta peptide (Abeta) oligomerization and deposition, and enhanced neurogenesis. Moreover, increased levels of IL-4 improved spatial learning, promoted phosphorylation of N-methyl-D-aspartate receptor subunit 2B at Tyr 1472, and enhanced its cell surface retention both in vivo and in vitro. Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Abeta-mediated treatment of AD.

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Interleukin‐4 blocks thapsigargin‐induced cell death in rat rod photoreceptors: Involvement of cAMP/PKA pathway

Cited by 12 publications

References 54 publications

Interleukin 4 Leads to Sustained Phosphorylation of the STAT6 and ERK Pathways in the Retina and Disrupts Subcortical Visual Circuitry in Rodents

Interleukin 4 Leads to Sustained Phosphorylation of the STAT6 and ERK Pathways in the Retina and Disrupts Subcortical Visual Circuitry in Rodents

PKA‐mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S‐nitrosylation

CNS expression of anti‐inflammatory cytokine interleukin‐4 attenuates Alzheimer's disease‐like pathogenesis in APP+PS1 bigenic mice

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