Down-regulation of caveolin-1, an inhibitor of transforming growth factor-beta signaling, in acute allergen-induced airway remodeling.
Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming growth factor-beta (TGF-beta). The scaffolding protein caveolin-1 (cav1) can inhibit the activity of TGF-beta, perhaps by forming membrane invaginations that enfold TGF-beta receptors. The study goals were 1) to evaluate how allergen challenge affects lung expression of cav1 and the density of caveolae in vivo 2) to determine whether reduced cav1 expression is mediated by interleukin (IL)-4 and 3) to measure the effects of decreased expression of cav1 on TGF-beta signaling. C57BL/6J, IL-4-deficient mice, and cav1-deficient mice, sensitized by intraperitoneal injections of phosphate-buffered saline or ovalbumin (OVA) at days 0 and 12, received intranasal phosphate-buffered saline or OVA challenges at days 24, 26, and 28. Additionally, another group of C57BL/6J mice received IL-4 by intratracheal instillation for 7 days. We confirmed that the OVA-allergen challenge increased eosinophilia and T-helper type 2-related cytokine levels (IL-4, IL-5, and IL-13) in bronchoalveolar lavage. Allergen challenge reduced lung cav1 mRNA abundance by 40%, cav1 protein by 30%, and the number of lung fibroblast caveolae by 50%. Administration of IL-4 in vivo also substantially decreased cav1 expression. In contrast, the allergen challenge did not decrease cav1 expression in IL-4-deficient mice. The reduced expression of cav1 was associated with activation of TGF-beta signaling that was further enhanced in OVA-sensitized and challenged cav1-deficient mice. This study demonstrates a previously unknown modulation of TGF-beta signaling by IL-4, via cav1, suggesting novel therapeutic targets for controlling the effects of TGF-beta and thereby ameliorating pathological airway remodeling.
Le Saux
Claude Jourdan
CJ
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA. claude@pbrc.hawaii.edu
Teeters
Kelsa
K
Miyasato
Shelley K
SK
Hoffmann
Peter R
PR
Bollt
Oana
O
Douet
Vanessa
V
Shohet
Ralph V
RV
Broide
David H
DH
Tam
Elizabeth K
EK
D000485:Allergens / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018893:Bronchoalveolar Lavage; D051242:Caveolin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000485:Allergens; D051242:Caveolin 1; D007378:Interleukins; D016212:Transforming Growth Factor beta