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



The regulation of bronchial epithelial TJs by TH2 cells and their cytokines and their involvement in epigenetic regulation of barrier function were investigated.



The 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.



HBECs 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.



Our 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.
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Paulina
P
Wawrzyniak
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Marcin
M
Wawrzyniak
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Kerstin
K
Wanke
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Milena
M
Sokolowska
Institute of Immunology, Zagreb, Croatia.
Kreso
K
Bendelja
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Beate
B
Rückert
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Anna
A
Globinska
Department of Medicine, Jagiellonian University Medical College, Krakow, Poland.
Bogdan
B
Jakiela
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Jeannette I
JI
Kast
Department of Pneumology, University Hospital Freiburg, Freiburg, Germany.
Marco
M
Idzko
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Mübeccel
M
Akdis
Department of Medicine, Jagiellonian University Medical College, Krakow, Poland.
Marek
M
Sanak
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland. Electronic address: akdiasac@siaf.uzh.ch.
Cezmi A
CA
Akdis
D000328:Adult; D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*
D016207:Cytokines; D012333:RNA, Messenger; D006655:Histone Deacetylases
Asthma; IL-13; IL-4; T(H)2 cells; bronchial epithelial cells; epigenetic; histone deacetylase; tight junctions