Selective upregulation of platelet-derived growth factor α receptors by transforming growth factor β in scleroderma fibroblasts

Abstract

Transforming growth factor β(TGF-β), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-α receptor arm of that system. TGF-β effects on PDGF α receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-β. In newborn foreskin fibroblasts, PDGF α receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-β (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF α receptor number by TGF-β occurred consistently with SSc fibroblasts and low concentrations of TGF-β (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of α receptor subunit by TGF-β in SSc fibroblasts correlated with increased new PDGF α receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-β had no effect on either synthesis or mRNA expression of α receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-β correlated positively with effects of TGF-β on expression of α receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-β selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/α receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.