Selective Upregulation of Platelet-derived Growth Factor c~ Receptors by Transforming Growth Factor/~ in Scleroder Fibroblasts

Transforming growth factor B (TGF-~), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-c~ receptor arm of that system. TGF-~ effects on PDGF ot 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-~. In newborn foreskin fibroblasts, PDGF c~ receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-B (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF c~ receptor number by TGF-B occurred consistently with SSc fibroblasts and low concentrations of TGF-~/(0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of ot receptor subunit by TGF-~ in SSc fibroblasts correlated with increased new PDGF ot 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-B had no effect on either synthesis or mRNA expression of c~ receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-B correlated positively with effects of TGF-~ on expression of o~ 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-B 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/ol receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.