Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts.
Integrin alphavbeta5 is a receptor for vitronectin, a plasma glycoprotein that is also distributed in extracellular matrix of various tissues. Matrix-bound vitronectin has the potential to stabilize the active form of plasminogen activator inhibitor-1, resulting in the inhibition of the plasmin-mediated pericellular proteolytic cascade. In this study, we compared the levels of alphavbeta5 and matrix-bound vitronectin between normal and scleroderma fibroblasts and investigated the association with fibrosis. We demonstrated that alphavbeta5 was up-regulated on scleroderma fibroblasts. The up-regulated alphavbeta5 contributed to the increase in vitronectin-binding ability in scleroderma fibroblasts, which led to the vitronectin-dependent activation of plasminogen activator inhibitor-1. In immunohistochemistry, the alphav and beta5 subunits were stained strongly on scleroderma fibroblasts and the amount of vitronectin was increased in the pericellular matrix of those cells. The transient overexpression of alphavbeta5 on normal fibroblasts enhanced the human alpha2(I) collagen promoter activity through Sp-1 and Smad3 as well as the vitronectin-dependent plasminogen activator inhibitor-1 activity. This effect on the promoter activity was also observed in the absence of vitronectin and completely disappeared in the presence of anti-alphavbeta5 antibody. These results indicate that the up-regulated alphavbeta5 may contribute to the phenotypical alteration of scleroderma fibroblasts, while at the same time suppressing the plasmin-mediated pericellular proteolytic cascade.
Asano
Yoshihide
Y
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Ihn
Hironobu
H
Yamane
Kenichi
K
Kubo
Masahide
M
Tamaki
Kunihiko
K
D015152:Blotting, Northern; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000096:biosynthesis*; D009154:Mutation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D019030:Receptors, Vitronectin / Q000096:biosynthesis*; D045743:Scleroderma, Diffuse / Q000378:metabolism*; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D019096:Vitronectin / Q000378:metabolism
D024042:Collagen Type I; D004268:DNA-Binding Proteins; D016023:Integrins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019030:Receptors, Vitronectin; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D019096:Vitronectin; C064660:integrin alphaVbeta5