Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblasts.
The biological effect of cytokines is mainly determined by the cytokine-receptor interaction, which is modulated by the concentration and the activity of cytokines and/or their receptors. Because alphav-containing integrins can bind to and/or activate latent TGF-beta, these integrins have been thought to be involved in the pathogenesis of fibrotic disorders. Our recent observations that alphavbeta5 is up-regulated in scleroderma fibroblasts and that the transient overexpression of alphavbeta5 increases the human alpha2(I) collagen gene expression in normal fibroblasts suggest the involvement of alphavbeta5 in the self-activation system in scleroderma fibroblasts. In this study, we established stable transfectants with alphavbeta5 using normal dermal fibroblasts and demonstrated that such cells differentiated into myofibroblasts by the stimulation of autocrine TGF-beta. This observation is explained by 1) alphavbeta5 recruiting latent TGF-beta1 on the cell surface, 2) endogenous active TGF-beta localizing on the cell surface, and 3) alphavbeta5 interacting with TGF-beta receptors. Furthermore, blockade of alphavbeta5 reversed the myofibroblastic phenotype in scleroderma fibroblasts. These data identify a novel mechanism for the establishment of autocrine TGF-beta signaling in dermal fibroblasts by the up-regulation of alphavbeta5 and suggest the possibility of regulating fibrotic disorders, especially scleroderma, by targeting this integrin.
Asano
Yoshihide
Y
Department of Dermatology, University of Tokyo, Tokyo, Japan.
Ihn
Hironobu
H
Yamane
Kenichi
K
Jinnin
Masatoshi
M
Tamaki
Kunihiko
K
D030201:Activin Receptors, Type I / Q000378:metabolism; D019898:Autocrine Communication; D015152:Blotting, Northern; D002448:Cell Adhesion; D002454:Cell Differentiation; D002478:Cells, Cultured; D020405:Dermis / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000503:physiopathology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016023:Integrins; D018125:Receptors, Transforming Growth Factor beta; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C064660:integrin alphaVbeta5; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II