Down-regulation of Caveolin-1, an Inhibitor of Transforming Growth Factor-β Signaling, in Acute Allergen-induced Airway Remodeling

Abstract

Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming growth factor-␤ (TGF-␤). The scaffolding protein caveolin-1 (cav1) can inhibit the activity of TGF-␤, perhaps by forming membrane invaginations that enfold TGF-␤ 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-␤ 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-␤ signaling that was further enhanced in OVA-sensitized and challenged cav1-deficient mice. This study demonstrates a previously unknown modulation of TGF-␤ signaling by IL-4, via cav1, suggesting novel therapeutic targets for controlling the effects of TGF-␤ and thereby ameliorating pathological airway remodeling.Asthma is often associated with structural changes in the bronchioles, commonly referred to as airway remodeling (1). These alterations result from injury and repair processes regulated by several mediators, such as T-helper type 2 (Th2) 2 cytokines and transforming growth factor ␤ (TGF-␤). Cytokines modulate subepithelial fibrosis by regulating fibroblast proliferation and differentiation and by stimulating synthesis and stabilization of the proteins that constitute the extracellular matrix. In vitro, Th2-related cytokines regulate the secretion of connective tissue proteins, including collagens, fibronectin, and tenascin, all of which are involved in the thickening of the airway basement membrane (2-7). Interleukin-4 (IL-4) and IL-13 levels are notably increased in bronchoalveolar lavage (BAL) fluid of asthmatic patients (3,8). Inhibitors of IL-4 and IL-13 prevent the development of fibrosis (9, 10). IL-4-and IL-13-deficient mice develop less subepithelial fibrosis and goblet cell hyperplasia after allergen challenge, compared with their normal counterparts (11, 12), indicating the importance of IL-4 and IL-13 in driving airway remodeling.TGF-␤, one of the most potent regulators of inflammation and connective tissue synthesis, plays an integral role in the development of airway remodel...

Reversible remodeling of lung tissue during hibernation in the Syrian hamster

“…High expression of TGF-, another marker for tissue remodeling, was also found during early torpor and also at early arousal, which was then reduced to the euthermic level at the late arousal phase (Fig.5B). Caveolin-1 expression, as part of the TGF- signaling pathway was also measured (Le Saux et al, 2008b). The expression was reduced to half of the euthermic expression during the late torpor phase, and it reached its highest point during early arousal (Fig.6D).…”

“…Caveolin-1-deficient mice show lung abnormalities, with thickened alveolar septa and hypercellularity, and they are exercise intolerant (Razani et al, 2001). Caveolin-1 inhibits the activity of TGF-, perhaps by forming membrane invaginations that enfold TGF- receptors (Le Saux et al, 2008a); however, a higher expression of TGF- has shown to downregulate caveolin-1 expression in cultured endothelial cells (Igarashi et al, 2009). In our experiment lower expression of caveolin-1 was accompanied by higher expression of TGF- as a remodeling marker.…”

Minocycline Blocks Asthma-associated Inflammation in Part by Interfering with the T Cell Receptor-Nuclear Factor κB-GATA-3-IL-4 Axis without a Prominent Effect on Poly(ADP-ribose) Polymerase

“…The cells were maintained at 37°C, and culture supernatants were collected after 96 h for the quantification of OVA-specific IgE by sandwich ELISA (Serotec) as described above. Ferric Reducing Ability Assay and Poly(ADP-ribosyl)ation in Vitro-The ferric reducing ability of minocycline was measured essentially as described previously (22). The antioxidant capacity of minocycline was calculated from the linear calibration curve and expressed as mmol FeSO4 equivalents.…”

The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties

“…The physiological importance of cav1 in lungs has recently been highlighted by the description of its dysregulation in pulmonary disorders such as interstitial fibrosis (48) and bronchiolization in lung fibrosis (29,43) and in airway remodeling in an allergen-challenged mouse model (23). In these pathologies, decreased expression of the gene encoding cav1 (cav1) was associated with enhanced TGF-␤ signaling and increased collagen deposition.…”