title: Caveolin-1 controls airway epithelial barrier function. Implications for asthma.
abstract: The molecular basis for airway epithelial fragility in asthma has remained unclear. We investigated whether the loss of caveolin-1, the major component of caveolae and a known stabilizer of adherens junctions, contributes to epithelial barrier dysfunction in asthma. We studied the expression of caveolin-1 and adhesion molecules E-cadherin and β-catenin in airway sections, and we cultured bronchial epithelial cells from patients with asthma and from healthy control subjects. To determine the functional role of caveolin-1, we investigated the effects of caveolin-1 up-regulation and down-regulation on E-cadherin expression, barrier function, and proallergic activity in the human bronchial epithelial cell lines 16HBE and BEAS-2B. The membrane expression of caveolin-1 was significantly lower in airway epithelia from patients with asthma than from subjects without asthma, and this lower expression was maintained in vitro upon air-liquid interface and submerged culturing. Importantly, reduced caveolin-1 expression was accompanied by a loss of junctional E-cadherin and β-catenin expression, disrupted epithelial barrier function, and increased levels of the proallergic cytokine thymic stromal lymphopoietin (TSLP). Furthermore, E-cadherin redistribution upon exposure to epidermal growth factor or house dust mite was paralleled by the internalization of caveolin-1 in 16HBE cells. These effects appear to be causally related, because the short, interfering RNA down-regulation of caveolin-1 resulted in the delocalization of E-cadherin and barrier dysfunction in 16HBE cells. Moreover, caveolin-1 overexpression improved barrier function and reduced TSLP expression in BEAS-2B cells. Together, our data demonstrate a crucial role for caveolin-1 in epithelial cell-cell adhesion, with important consequences for epithelial barrier function and the promotion of Th2 responses in asthma.
authors.affiliation: 1 University of British Columbia James Hogg Research Centre, Heart and Lung Institute, St. Paul's Hospital, Vancouver, British Columbia, Canada; and.
authors.forename: Tillie-Louise
authors.initials: TL
authors.lastname: Hackett
authors.forename: Harold G
authors.initials: HG
authors.lastname: de Bruin
authors.forename: Furquan
authors.initials: F
authors.lastname: Shaheen
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.forename: Antoon J
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002648:Child; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D039981:Pyroglyphidae / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D015820:Cadherins; D051242:Caveolin 1; D015815:Cell Adhesion Molecules; D051176:beta Catenin; D004815:Epidermal Growth Factor