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.