High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway

Recent studies have indicated that high-mobility group box 1 protein (HMGB1) and the receptor for advanced glycation end-products (RAGE) contribute to the pathogenesis of asthma. However, whether the activation of the HMGB1/RAGE axis mediates airway epithelial barrier dysfunction remains unknown. Th...

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Autores principales: HUANG, WUFENG, ZHAO, HAIJIN, DONG, HANGMING, WU, YUE, YAO, LIHONG, ZOU, FEI, CAI, SHAOXI
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829140/
https://www.ncbi.nlm.nih.gov/pubmed/27035254
http://dx.doi.org/10.3892/ijmm.2016.2537
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author HUANG, WUFENG
ZHAO, HAIJIN
DONG, HANGMING
WU, YUE
YAO, LIHONG
ZOU, FEI
CAI, SHAOXI
author_facet HUANG, WUFENG
ZHAO, HAIJIN
DONG, HANGMING
WU, YUE
YAO, LIHONG
ZOU, FEI
CAI, SHAOXI
author_sort HUANG, WUFENG
collection PubMed
description Recent studies have indicated that high-mobility group box 1 protein (HMGB1) and the receptor for advanced glycation end-products (RAGE) contribute to the pathogenesis of asthma. However, whether the activation of the HMGB1/RAGE axis mediates airway epithelial barrier dysfunction remains unknown. Thus, the aim of this study was to examine the effects of HMGB1 and its synergistic action with interleukin (IL)-1β on airway epithelial barrier properties. We evaluated the effects of recombinant human HMGB1 alone or in combination with IL-1β on ionic and macromolecular barrier permeability, by culturing air-liquid interface 16HBE cells with HMGB1 to mimic the differentiated epithelium. Western blot analysis and immunofluorescence staining were utilized to examine the level and structure of major junction proteins, namely E-cadherin, β-catenin, occludin and claudin-1. Furthermore, we examined the effects of RAGE neutralizing antibodies and mitogen-activated protein kinase (MAPK) inhibitors on epithelial barrier properties in order to elucidate the mechanisms involved. HMGB1 increased FITC-dextran permeability, but suppressed epithelial resistance in a dose-and time-dependent manner. HMGB1-mediated barrier hyperpermeability was accompanied by a disruption of cell-cell contacts, the selective downregulation of occludin and claudin-1, and the redistribution of E-cadherin and β-catenin. HMGB1 in synergy with IL-1β induced a similar, but greater barrier hyperpermeability and induced the disruption of junction proteins. Furthermore, HMGB1 elicited the activation of the RAGE/extracellular signal-related kinase (ERK)1/2 signaling pathway, which correlated with barrier dysfunction in the 16HBE cells. Anti-RAGE antibody and the ERK1/2 inhibitor, U0126, attenuated the HMGB1-mediated changes in barrier permeability, restored the expression levels of occludin and claudin-1 and pevented the redistribution of E-cadherin and β-catenin. Taken together, the findings of our study demonstrate that HMGB1 is capable of inducing potent effects on epithelial barrier function and that RAGE/ERK1/2 is a key signaling pathway involved in the crosstalk between formations of junction proteins and epithelial barrier dysfunction.
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spelling pubmed-48291402016-04-13 High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway HUANG, WUFENG ZHAO, HAIJIN DONG, HANGMING WU, YUE YAO, LIHONG ZOU, FEI CAI, SHAOXI Int J Mol Med Articles Recent studies have indicated that high-mobility group box 1 protein (HMGB1) and the receptor for advanced glycation end-products (RAGE) contribute to the pathogenesis of asthma. However, whether the activation of the HMGB1/RAGE axis mediates airway epithelial barrier dysfunction remains unknown. Thus, the aim of this study was to examine the effects of HMGB1 and its synergistic action with interleukin (IL)-1β on airway epithelial barrier properties. We evaluated the effects of recombinant human HMGB1 alone or in combination with IL-1β on ionic and macromolecular barrier permeability, by culturing air-liquid interface 16HBE cells with HMGB1 to mimic the differentiated epithelium. Western blot analysis and immunofluorescence staining were utilized to examine the level and structure of major junction proteins, namely E-cadherin, β-catenin, occludin and claudin-1. Furthermore, we examined the effects of RAGE neutralizing antibodies and mitogen-activated protein kinase (MAPK) inhibitors on epithelial barrier properties in order to elucidate the mechanisms involved. HMGB1 increased FITC-dextran permeability, but suppressed epithelial resistance in a dose-and time-dependent manner. HMGB1-mediated barrier hyperpermeability was accompanied by a disruption of cell-cell contacts, the selective downregulation of occludin and claudin-1, and the redistribution of E-cadherin and β-catenin. HMGB1 in synergy with IL-1β induced a similar, but greater barrier hyperpermeability and induced the disruption of junction proteins. Furthermore, HMGB1 elicited the activation of the RAGE/extracellular signal-related kinase (ERK)1/2 signaling pathway, which correlated with barrier dysfunction in the 16HBE cells. Anti-RAGE antibody and the ERK1/2 inhibitor, U0126, attenuated the HMGB1-mediated changes in barrier permeability, restored the expression levels of occludin and claudin-1 and pevented the redistribution of E-cadherin and β-catenin. Taken together, the findings of our study demonstrate that HMGB1 is capable of inducing potent effects on epithelial barrier function and that RAGE/ERK1/2 is a key signaling pathway involved in the crosstalk between formations of junction proteins and epithelial barrier dysfunction. D.A. Spandidos 2016-05 2016-03-24 /pmc/articles/PMC4829140/ /pubmed/27035254 http://dx.doi.org/10.3892/ijmm.2016.2537 Text en Copyright: © Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
HUANG, WUFENG
ZHAO, HAIJIN
DONG, HANGMING
WU, YUE
YAO, LIHONG
ZOU, FEI
CAI, SHAOXI
High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway
title High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway
title_full High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway
title_fullStr High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway
title_full_unstemmed High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway
title_short High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway
title_sort high-mobility group box 1 impairs airway epithelial barrier function through the activation of the rage/erk pathway
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829140/
https://www.ncbi.nlm.nih.gov/pubmed/27035254
http://dx.doi.org/10.3892/ijmm.2016.2537
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