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-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. 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. Asthma is often associated with structural changes in the bronchioles, commonly referred to as airway remodeling (1Bousquet J. Jeffery P.K. Busse W.W. Johnson M. Vignola A.M. Am. J. Respir. Crit. Care Med. 2000; 161: 1720-1745Crossref PubMed Scopus (1560) Google Scholar). 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The Smad complex then translocates to the nucleus where, together with DNA-binding cofactors, it regulates the transcription of target genes (21Macias-Silva M. Abdollah S. Hoodless P.A. Pirone R. Attisano L. Wrana J.L. Cell. 1996; 87: 1215-1224Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar, 23Nakao A. Imamura T. Souchelnytskyi S. Kawabata M. Ishisaki A. Oeda E. Tamaki K. Hanai J. Heldin C.H. Miyazono K. ten Dijke P. EMBO J. 1997; 16: 5353-5362Crossref PubMed Scopus (916) Google Scholar). TGF-β-mediated phosphorylation of Smad2 can be prevented by caveolin-1 (cav1), one of three members of the caveolin protein family (24Razani B. Zhang X.L. Bitzer M. von Gersdorff G. Bottinger E.P. Lisanti M.P. J. Biol. Chem. 2001; 276: 6727-6738Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). 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We that the effects of during regulate the expression and of cav1 and thereby the signaling and pathological effects of We used a of airway inflammation to that modulation of cav1 expression is mediated by instillation of IL-4 in cav1 in to in cav1 expression in IL-4-deficient mice. We then that TGF-β signaling is by allergen challenge in cav1-deficient mice compared with mice. and mice were from The The for the cav1 mice is a of C57BL/6J and The were then to C57BL/6J mice for The were a by the Care and of the of Cell and lung were from and mice. were with and type I in with and and with in at for The was and the were of with The was on the tissue for a of three The cell was one of and at for The were in with with a and at were used at and and The were for with of IL-4 2 of TGF-β or IL-4 number Allergen and of C57BL/6J and cav1-deficient mice were sensitized by intraperitoneal injections on days 0 and with of phosphate-buffered saline or of OVA of in of to mice were challenged with intranasal of of or OVA on days 24, 26, and the mice were by and was lung tissue was used for and and lung tissue was for and protein whether cav1 was mediated by IL-4, mice were by intraperitoneal of and to intratracheal with or IL-4 from of as by C. M. J. Allergy Clin. Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar). and protein were for cytokine and mRNA abundance or of TGF-β and connective tissue proteins, in and intratracheal with of fluid was from and at at for The was at for cytokine The cell was in of to determine cell were with a of a were as previously R.K. J. M. M. E. Am. J. Respir. Cell Mol. Biol. 2003; PubMed Scopus Google Scholar). IL-4 and levels were in fluid to the IL-13 levels were IL-13 of fluid was number was for In was with and to the to to the of the of in the and was from cell or tissue the were with of I at for was for The of expression of cav1 was by cav1 Foster and the protein was by of lung on in of and were at and protein in were by the protein was with at for on and of a The protein was to membrane and with including and Cell were of were and This was used to measure the from of to to be The of the target was to that of the to a of proteins of on an lung tissue or cell were by in in The were then in with in in a and in were on with and and on a at at were by to the of the and the number of caveolae was of cell membrane and expression is often regulated by IL-4 a that the of the cav1 in used to a M. C. 1999; PubMed Scopus Google with lung were in for at was by with The were with and in and for at The was for at and the were at for in and The were in and at for The was at to the were with or with normal was in the by in at for with was on the for the of the cav1 and These the the the cav1 The were by in from The the in cav1 was the as by the The was in and or of was with the for at the the were with of on for the was The were used in on cav1 and and as previously M. D. Jr., 2005; PubMed Scopus (149) Google and TGF-β activation of the TGF-β was by the of expression of in vivo and by the of expression of the the of Smad in by for were from lung tissue and were in with were the as by the The were for activity after a activity a was of were in in and with of the were as a was by to the of the were to the of the lung The for the and was as a and 2 a in an in in all and all and increased in all and We used the for 0 to and 2 the and The for the were as the was used to determine compared was and were determine whether cav1 in airway remodeling on its with the TGF-β signaling cav1 expression and caveolae in the OVA-allergen challenge K. M. Am. J. Respir. Crit. Care Med. 2003; PubMed Scopus Google Scholar). an with of confirmed the inflammation in the OVA-sensitized and challenged mice in by in to mice. allergen cell increased from of OVA-allergen challenge a eosinophilia In IL-4, IL-5, and IL-13 levels were increased in fluid from OVA-sensitized and challenged mice, and TGF-β in of or and cav1-deficient mice or or IL-4 in a We then the expression of cav1 and formation of by the of cav1 mRNA in the lung of OVA-sensitized and challenged was reduced by compared with and challenged mice a decrease in cav1 protein which to a decreased number of caveolae, as by In a group of was sensitized with OVA and challenged with as and The Th2-related cytokine and the of cav1 expression were to in and challenged mice. did not further mice in IL-4 the of of the cav1 was with the and transcription factor and The in several family at to at to and at to and are by a wide of growth and is the signal in to IL-4 or IL-13 K. J. 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We whether cav1 expression was mediated by IL-4 or were with IL-4, and receptor In that cav1 was and not and We then the in vivo of cav1 expression in mice intratracheal IL-4 and in IL-4-deficient mice. an in cell 2 0 IL-4, and TGF-β in fluid of mice, compared with Cav1 mRNA and cav1 protein levels were reduced by in the of mice with intratracheal instillation of IL-4, compared with mice contrast, the abundance of cav1 mRNA was not in OVA-sensitized and challenged IL-4-deficient mice compared with and challenged mice IL-4-deficient mice did not develop a after allergen challenge the and IL-4, to determine whether to the cav1 in as a for IL-4 of cav1 transcription. was with on from that previously with IL-4, or with cav1 from of mice did not of the cav1 and of cav1 was by in the and in OVA-sensitized and challenged compared with lung to the cav1 in vivo in to IL-4 and OVA-allergen of to the cav1 were with from a of the of the cav1 that the to was by of with the on the cav1 as as a not the of in cell of a were from and their to IL-4 was compared with from normal mice. In the of transcription cav1 expression was not in lung These that the of cav1 in allergen is and most via signaling. TGF-β with cav1 in was at levels in fluid of and challenged mice was increased in OVA-sensitized and mice Smad2 is a for TGF-β and an of the to which TGF-β signaling is Smad2 activation is by its the of OVA challenge on TGF-β activation by the of in lung by was in lung a in the of was in the of OVA-sensitized and challenged mice, indicating activation of the TGF-β signaling the was increased in mice intratracheal IL-4 not in IL-4-deficient mice. These an the of cav1 expression and the activation of TGF-β signaling. We whether the of cav1 result in enhanced TGF-β signaling cav1-deficient mice were or OVA-sensitized and TGF-β in cav1-deficient allergen the of mice were to in mice of OVA-allergen challenge a in cell and eosinophilia compared with that in group In IL-4, IL-5, and TGF-β levels were increased in OVA-sensitized challenged compared with the group contrast, OVA and challenge an in the of in mice as compared with The of Smad2 was the of These that in the of cav1 TGF-β signaling was enhanced in OVA-sensitized and challenged mice. In the activity of Smad was in the lung of the in TGF-β IL-4 in the TGF-β IL-4 lung fibroblasts, the activity was enhanced compared with TGF-β These confirmed that in or with reduced expression lung with TGF-β signaling was in an in expression. whether enhanced activation of TGF-β signaling in enhanced lung fibrosis, the on lung tissue in and and mice. an in the in compared with mice for mice a substantially did the mice the increased deposition was the and in the as as the We that cav1 be and associated with increased TGF-β signaling in an of allergen We confirmed that increased levels of IL-4, were associated with decreased expression of cav1 and activation of TGF-β signaling. The decreased expression of cav1 was not in IL-4-deficient mice. of IL-4 in a of cav1 mediated by on the cav1 We confirmed in vivo that cav1 was In OVA-sensitized and challenged mice an enhanced activation of the TGF-β signaling compared with mice, in a on the of to their role in or A. S. 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Care Med. 1997; 156: 642-647Crossref PubMed Scopus (383) Google Scholar, 17Nakao A. Sagara H. Setoguchi Y. Okada T. Okumura K. Ogawa H. Fukuda T. J. Allergy Clin. Immunol. 2002; 110: 873-878Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 18Sagara H. Okada T. Okumura K. Ogawa H. Ra C. Fukuda T. Nakao A. J. Allergy Clin. Immunol. 2002; 110: 249-254Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). TGF-β is associated with the of In that an increased of TGF-β was in an allergen challenge The of the TGF-β signaling by cav1 has in reduced cav1 expression was in with increased TGF-β activity in fibrosis Zhang Y. F. E. X. N. A.M. J. Exp. Med. PubMed Scopus Google Scholar). fibrosis is a inflammation associated with asthmatic patients also inflammation associated with subepithelial the of cav1 in fibrosis has not associated with as shown in In with a of increased levels of TGF-β and decreased expression of cav1 also shown W. L. J. A. C. PubMed Scopus Google Scholar). In that in fibrosis, was involved in the enhanced TGF-β signaling not in the of cav1 expression X.L. N. T. A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Zhang and X.L. N. T. A. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google that the of TGF-β in the of was the TGF-β signaling. In the of TGF-β were associated TGF-β signaling. the that IL-4 the expression of cav1, a TGF-β effects of TGF-β by caveolin a therapeutic in such as the of caveolae and its is an ameliorating airway remodeling and We for and We are also to and for