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J. Biol. Chem., Vol. 283, Issue 9, 5760-5768, February 29, 2008

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

Claude Jourdan Le Saux¹, Kelsa Teeters, Shelley K. Miyasato, Peter R. Hoffmann, Oana Bollt, Vanessa Douet, Ralph V. Shohet, David H. Broide^¶, and Elizabeth K. Tam

From the Departments of Cell and Molecular Biology and Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813 and the ^¶Department of Medicine, University of California, San Diego, California 92093

Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming growth factor-β (TGF-β). The scaffolding protein caveolin-1 (cav1) can inhibit the activity of TGF-β, perhaps by forming membrane invaginations that enfold TGF-β 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-β 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-β signaling that was further enhanced in OVA-sensitized and challenged cav1-deficient mice. This study demonstrates a previously unknown modulation of TGF-β signaling by IL-4, via cav1, suggesting novel therapeutic targets for controlling the effects of TGF-β and thereby ameliorating pathological airway remodeling.

Received for publication, February 22, 2007 , and in revised form, November 29, 2007.

^* This work was supported by the National Institutes of Health Grants G12RR0003061, P20RR016467, RR16453, and HL073449, the American Lung Association of Hawaii, and the Hawaii Community Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 651 Ilalo St. BSB 222, Honolulu, HI 96813. Tel.: 808-692-1511; Fax: 808-692-1970; E-mail: claude{at}pbrc.hawaii.edu.

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				O. Le Saux, K. Teeters, S. Miyasato, J. Choi, G. Nakamatsu, J. A. Richardson, B. Starcher, E. C. Davis, E. K. Tam, and C. Jourdan-Le Saux The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L1007 - L1017. [Abstract] [Full Text] [PDF]