Regular ArticlesIncreased 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 αv-containing integrins can bind to and/or activate latent TGF-β, these integrins have been thought to be involved in the pathogenesis of fibrotic disorders. Our recent observations that αvβ5 is up-regulated in scleroderma fibroblasts and that the transient overexpression of αvβ5 increases the human α2(I) collagen gene expression in normal fibroblasts suggest the involvement of αvβ5 in the self-activation system in scleroderma fibroblasts. In this study, we established stable transfectants with αvβ5 using normal dermal fibroblasts and demonstrated that such cells differentiated into myofibroblasts by the stimulation of autocrine TGF-β. This observation is explained by 1) αvβ5 recruiting latent TGF-β1 on the cell surface, 2) endogenous active TGF-β localizing on the cell surface, and 3) αvβ5 interacting with TGF-β receptors. Furthermore, blockade of αvβ5 reversed the myofibroblastic phenotype in scleroderma fibroblasts. These data identify a novel mechanism for the establishment of autocrine TGF-β signaling in dermal fibroblasts by the up-regulation of αvβ5 and suggest the possibility of regulating fibrotic disorders, especially scleroderma, by targeting this integrin.