Increased expression of integrin αvβ5 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 alpha v-containing integrins can bind to and/or activate latent TGF-beta, these integrins have been thought to he involved in the pathogenesis of fibrotic disorders. Our recent observations that alpha v beta 5 is up-regulated in scleroderma fibroblasts and that the transient overexpression of alpha v beta 5 increases the human alpha 2(I) collagen gene expression in normal fibroblasts suggest the involvement of alpha v beta 5 in the self-activation system in scleroderma fibroblasts. In this study, we established stable transfectants with alpha v beta 5 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) alpha v beta 5 recruiting latent TGF-beta 1 on the cell surface, 2) endogenous active TGF-beta localizing on the cell surface, and 3) alpha v beta 5 interacting with. TGF-beta receptors. Furthermore, blockade of alpha v beta 5 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 alpha v beta 5 and suggest the possibility of regulating fibrotic disorders, especially scleroderma, by targeting this integrin.