Interleukin-4 blocks proliferation of retinal progenitor cells and increases rod photoreceptor differentiation through distinct signaling pathways

Silva, Ana Gabriela Ledo Santos da; Campello-Costa, Paula; Linden, Rafael; Sholl‐Franco, Alfred

doi:10.1016/j.jneuroim.2008.03.003

Cited by 19 publications

(22 citation statements)

References 52 publications

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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: 85%

“…Since IL-4R was identified in glial cells [4,6], we decided to evaluate the effect of a single intravitreous treatment with IL-4 upon glial cell activation. Retinal cytoarchitecture is well preserved and no pyknotic nuclei or inflammatory cells were detected in either the PBS-or IL-4-treated group (Fig.…”

Section: Effect Of a Single Il-4 Intravitreal Injection On Glial Cellmentioning

confidence: 99%

“…The cellular response to this cytokine depends on the activation of the IL-4 receptor (IL-4R) containing the α subunit (IL-4Rα) [3]. In the CNS, both IL-4 and IL-4Rα are localized in neuronal and glial cells [4][5][6]. Signal transduction through IL-4Rs involves 3 major pathways: JAK-STAT6, Raf-MEK-ERK and PI3K-Akt [1,3].…”

Section: Introductionmentioning

confidence: 99%

“…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: 85%

Section: Effect Of a Single Il-4 Intravitreal Injection On Glial Cellmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…24 Briefly, 2-day-old rats were killed by decapitation, the eyeballs were removed, and the retinas dissected free from scleral tissue and RPE using a calcium-and magnesium-free balanced salt solution (CMF). The retinas were cut into fragments of approximately 1 mm 2 in complete BME supplemented with 2 mM L-glutamine, 100 lg/mL streptomycin sulfate, 100 U/mL penicillin G, 20 mM HEPES, and 5% fetal calf serum.…”

Section: Retinal Tissue Culturementioning

confidence: 99%

In Vitro Effects of Bevacizumab Treatment on Newborn Rat Retinal Cell Proliferation, Death, and Differentiation

Miguel

Matsuda

Portes

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Vascular endothelial growth factor (VEGF) is an important signal protein in vertebrate nervous development, promoting neurogenesis, neuronal patterning, and glial cell growth. Bevacizumab, an anti-VEGF agent, has been extensively used for controlling pathological retinal neovascularization in adult and newborn patients, although its effect on the developing retina remains largely unknown. The purpose of this study was to investigate the effect of bevacizumab on cell death, proliferation, and differentiation in newborn rat retina. METHODS.Retinal explants of sixty 2-day-old Lister hooded rats were obtained after eye enucleation and maintained in culture media with or without bevacizumab for 2 days. Immunohistochemical staining was assessed against proliferating cell nuclear antigen (PCNA, to detect cell proliferation); caspase-3 and beclin-1 (to investigate cell death); and vimentin and glial fibrillary acidic protein (GFAP, markers of glial cells). Gene expressions were quantified by real-time reverse-transcription polymerase chain reaction. Results from treatment and control groups were compared.RESULTS. No significant difference in the staining intensity (on immunohistochemistry) of PCNA, caspase-3, beclin-1, and GFAP, or in the levels of PCNA, caspase-3, beclin-1, and vimentin mRNA was observed between the groups. However, a significant increase in vimentin levels and a significant decrease in GFAP mRNA expression were observed in bevacizumab-treated retinal explants compared with controls.CONCLUSIONS. Bevacizumab did not affect cell death or proliferation in early developing rat retina but appeared to interfere with glial cell maturation by increasing vimentin levels and downregulating GFAP gene expression. Thus, we suggest anti-VEGF agents be used with caution in developing retinal tissue. (Invest Ophthalmol Vis Sci. 2012;53:7904-7911)

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

Adão-Novaes

Guterres

Silva

et al. 2009

J of Neuroscience Research

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Although the photoreceptors cell death is the main cause of some retinopathies diseases, the mechanisms involved in this process are poorly understood. The neuroprotective effects of interleukin-4 (IL-4) have been shown in several tissues, including retina. We demonstrate that treatment of rat retinal explants with IL-4 completely inhibited the thapsigargin-induced rod photoreceptor cell death after 24 hr in culture. We also showed that IL-4 receptor alpha subunit (IL-4Ralpha) is abundantly present in retina. Colocalization of IL-4Ralpha and rhodopsin indicate a direct effect of this cytokine in rod photoreceptor cells. Moreover, IL-4 increased the intracellular levels of cAMP in 7.4-fold, indicating that the neuroprotective effect of this cytokine was completely blocked by RpcAMP, an inhibitor of protein kinase (PKA). Our data demonstrate, for the first time, the neuroprotective effect of IL-4 through cAMP/PKA pathway in thapsigargin-induced photoreceptor cell death.

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Interleukin-4 blocks proliferation of retinal progenitor cells and increases rod photoreceptor differentiation through distinct signaling pathways

Cited by 19 publications

References 52 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

In Vitro Effects of Bevacizumab Treatment on Newborn Rat Retinal Cell Proliferation, Death, and Differentiation

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

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