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

  • Authors:
    • Wufeng Huang
    • Haijin Zhao
    • Hangming Dong
    • Yue Wu
    • Lihong Yao
    • Fei Zou
    • Shaoxi Cai
  • View Affiliations / Copyright

    Affiliations: Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1189-1198
    |
    Published online on: March 24, 2016
       https://doi.org/10.3892/ijmm.2016.2537
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Abstract

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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Copy and paste a formatted citation
Spandidos Publications style
Huang W, Zhao H, Dong H, Wu Y, Yao L, Zou F and Cai S: High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway. Int J Mol Med 37: 1189-1198, 2016.
APA
Huang, W., Zhao, H., Dong, H., Wu, Y., Yao, L., Zou, F., & Cai, S. (2016). High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway. International Journal of Molecular Medicine, 37, 1189-1198. https://doi.org/10.3892/ijmm.2016.2537
MLA
Huang, W., Zhao, H., Dong, H., Wu, Y., Yao, L., Zou, F., Cai, S."High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway". International Journal of Molecular Medicine 37.5 (2016): 1189-1198.
Chicago
Huang, W., Zhao, H., Dong, H., Wu, Y., Yao, L., Zou, F., Cai, S."High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway". International Journal of Molecular Medicine 37, no. 5 (2016): 1189-1198. https://doi.org/10.3892/ijmm.2016.2537
Copy and paste a formatted citation
x
Spandidos Publications style
Huang W, Zhao H, Dong H, Wu Y, Yao L, Zou F and Cai S: High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway. Int J Mol Med 37: 1189-1198, 2016.
APA
Huang, W., Zhao, H., Dong, H., Wu, Y., Yao, L., Zou, F., & Cai, S. (2016). High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway. International Journal of Molecular Medicine, 37, 1189-1198. https://doi.org/10.3892/ijmm.2016.2537
MLA
Huang, W., Zhao, H., Dong, H., Wu, Y., Yao, L., Zou, F., Cai, S."High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway". International Journal of Molecular Medicine 37.5 (2016): 1189-1198.
Chicago
Huang, W., Zhao, H., Dong, H., Wu, Y., Yao, L., Zou, F., Cai, S."High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway". International Journal of Molecular Medicine 37, no. 5 (2016): 1189-1198. https://doi.org/10.3892/ijmm.2016.2537
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