Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients

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• 作者：Paulina Wawrzyniak ; MSc^a ; Marcin Wawrzyniak ; PhD^a ; Kerstin Wanke ; PhD^a ; Milena Sokolowska ; MD ; PhD^a ; Kreso Bendelja ; PhD^d ; Beate Rü ; ckert ; Sci Tec^a ; Anna Globinska ; MSc^a ; Bogdan Jakiela ; MD ; PhD^b ; Jeannette I. Kast ; MSc^a ; Marco Idzko ; MD^c ; Mü ; beccel Akdis ; MD ; PhD^a ; Marek Sanak ; MD ; PhD^b ; Cezmi A. Akdis ; MD^a ; ^{akdiasac@siaf.uzh.ch}
• 关键词：Asthma ; bronchial epithelial cells ; epigenetic ; tight junctions ; TH2 cells ; IL-4 ; IL-13 ; histone deacetylase
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：93-103
• 全文大小：1467 K
• 卷排序：139

文摘

Tight junctions (TJs) form a barrier on the apical side of neighboring epithelial cells in the bronchial mucosa. Changes in their integrity might play a role in asthma pathogenesis by enabling the paracellular influx of allergens, toxins, and microbes to the submucosal tissue.ObjectiveThe regulation of bronchial epithelial TJs by TH2 cells and their cytokines and their involvement in epigenetic regulation of barrier function were investigated.MethodsThe expression, regulation, and function of TJs were determined in air-liquid interface (ALI) cultures of control and asthmatic primary human bronchial epithelial cells (HBECs) by means of analysis of transepithelial electrical resistance, paracellular flux, mRNA expression, Western blotting, and immunofluorescence staining.ResultsHBECs from asthmatic patients showed a significantly low TJ integrity in ALI cultures compared with HBECs from healthy subjects. TH2 cell numbers and levels of their cytokines, IL-4 and IL-13, decreased barrier integrity in ALI cultures of HBECs from control subjects but not in HBECs from asthmatic patients. They induced a physical separation of the TJs of adjacent cells in immunofluorescence staining of the TJ molecules occludin and zonula occludens-1. We observed that expression of histone deacetylases (HDACs) 1 and 9, and Silent information regulator genes (sirtuins [SIRTs]) 6 and 7 were significantly high in HBECs from asthmatic patients. IL-4 and IL-13 significantly increased the expression of HDACs and SIRTs. The role of HDAC activation on epithelial barrier leakiness was confirmed by HDAC inhibition, which improved barrier integrity through increased synthesis of TJ molecules in epithelium from asthmatic patients to the level seen in HBECs from control subjects.ConclusionOur data demonstrate that barrier leakiness in asthmatic patients is induced by TH2 cells, IL-4, and IL-13 and HDAC activity. The inhibition of endogenous HDAC activity reconstitutes defective barrier by increasing TJ expression.