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β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina

Diabetic retinopathy has recently become associated with complications similar to chronic inflammatory diseases. While it is clear that tumor necrosis factor- alpha (TNF-α) is increased in diabetes, the role of innate immunity is only recently being investigated. As such, we hypothesized that diabet...

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Autores principales: Berger, Elizabeth A., Carion, Thomas W., Jiang, Youde, Liu, Li, Chahine, Adam, Walker, Robert Jason, Steinle, Jena J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980247/
https://www.ncbi.nlm.nih.gov/pubmed/26888251
http://dx.doi.org/10.1038/icb.2016.21
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author Berger, Elizabeth A.
Carion, Thomas W.
Jiang, Youde
Liu, Li
Chahine, Adam
Walker, Robert Jason
Steinle, Jena J.
author_facet Berger, Elizabeth A.
Carion, Thomas W.
Jiang, Youde
Liu, Li
Chahine, Adam
Walker, Robert Jason
Steinle, Jena J.
author_sort Berger, Elizabeth A.
collection PubMed
description Diabetic retinopathy has recently become associated with complications similar to chronic inflammatory diseases. While it is clear that tumor necrosis factor- alpha (TNF-α) is increased in diabetes, the role of innate immunity is only recently being investigated. As such, we hypothesized that diabetes would increase toll-like receptor 4 (TLR4) signaling, which could be inhibited by a β-adrenergic receptor agonist (Compound 49b) previously shown to have anti-inflammatory actions. In order to investigate β-adrenergic receptor signaling and TLR4 in the diabetic retina, streptozotocin-injected diabetic mice, as well as human primary retinal endothelial cells (REC) and rat retinal Müller cells (rMC-1) exposed to high glucose (25mM), were treated with a novel β-adrenergic receptor agonist, Compound 49b (50nM), or PBS (control). TLR4 and its downstream signaling partners (MyD88, IRAK1, TRAF6, total and phosphorylated NF-κB) were examined. In addition, we assessed high mobility box group 1 (HMGB1) protein levels. Our data showed that diabetes or high glucose culture conditions significantly increased TLR4 and downstream signaling partners. Compound 49b was able to significantly reduce TLR4 and related molecules in the diabetic animal and retinal cells. HMGB1 was significantly increased in REC and Müller cells grown in high glucose, which was subsequently reduced with Compound 49b treatment. Our findings suggest that high glucose may increase HMGB1 levels that lead to increased TLR4 signaling. Compound 49b significantly inhibited this pathway providing a potential mechanism for its protective actions.
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spelling pubmed-49802472016-08-18 β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina Berger, Elizabeth A. Carion, Thomas W. Jiang, Youde Liu, Li Chahine, Adam Walker, Robert Jason Steinle, Jena J. Immunol Cell Biol Article Diabetic retinopathy has recently become associated with complications similar to chronic inflammatory diseases. While it is clear that tumor necrosis factor- alpha (TNF-α) is increased in diabetes, the role of innate immunity is only recently being investigated. As such, we hypothesized that diabetes would increase toll-like receptor 4 (TLR4) signaling, which could be inhibited by a β-adrenergic receptor agonist (Compound 49b) previously shown to have anti-inflammatory actions. In order to investigate β-adrenergic receptor signaling and TLR4 in the diabetic retina, streptozotocin-injected diabetic mice, as well as human primary retinal endothelial cells (REC) and rat retinal Müller cells (rMC-1) exposed to high glucose (25mM), were treated with a novel β-adrenergic receptor agonist, Compound 49b (50nM), or PBS (control). TLR4 and its downstream signaling partners (MyD88, IRAK1, TRAF6, total and phosphorylated NF-κB) were examined. In addition, we assessed high mobility box group 1 (HMGB1) protein levels. Our data showed that diabetes or high glucose culture conditions significantly increased TLR4 and downstream signaling partners. Compound 49b was able to significantly reduce TLR4 and related molecules in the diabetic animal and retinal cells. HMGB1 was significantly increased in REC and Müller cells grown in high glucose, which was subsequently reduced with Compound 49b treatment. Our findings suggest that high glucose may increase HMGB1 levels that lead to increased TLR4 signaling. Compound 49b significantly inhibited this pathway providing a potential mechanism for its protective actions. 2016-02-18 2016-08 /pmc/articles/PMC4980247/ /pubmed/26888251 http://dx.doi.org/10.1038/icb.2016.21 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Berger, Elizabeth A.
Carion, Thomas W.
Jiang, Youde
Liu, Li
Chahine, Adam
Walker, Robert Jason
Steinle, Jena J.
β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina
title β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina
title_full β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina
title_fullStr β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina
title_full_unstemmed β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina
title_short β-adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina
title_sort β-adrenergic receptor agonist, compound 49b, inhibits tlr4 signaling pathway in diabetic retina
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980247/
https://www.ncbi.nlm.nih.gov/pubmed/26888251
http://dx.doi.org/10.1038/icb.2016.21
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