DENSITY-DEPENDENT INHIBITORY EFFECT OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON HUMAN FIBROBLASTS INVOLVES THE DOWN-REGULATION OF PLATELET-DERIVED GROWTH-FACTOR ALPHA-RECEPTORS

We have previously found that transforming growth factor-beta1 (TGF-beta1) inhibits the mitogenic activity of platelet-derived growth factor (PDGF) in cultures of human neonatal fibroblasts in a density-dependent fashion. In the present investigation we determined the effect of TGF-beta1 on the PDGF alpha-receptor, which binds all PDGF isoforms, as well as on the beta-receptor, which binds only PDGF-BB with high affinity. We found that the inhibitory effect of TGF-beta1 on PDGF-AA-induced mitogenesis was density-dependent; when dense cell cultures were preincubated with TGF-beta1, there was an complete inhibition of H-3-thymidine incorporation, whereas the effect was less in sparse cultures. A similar density-dependent effect of TGF-beta1 was seen in PDGF-BB treated cells, although less pronounced. The binding of I-125-labeled PDGF-AA and PDGF-BB to the alpha-receptor was significantly reduced after treatment with TGF-beta1 in dense cultures, whereas the sparse cultures were less affected. A decrease of alpha-receptor mRNA was also seen. The levels of beta-receptor protein and mRNA were unaffected. We conclude that the growth inhibitory effect of TGF-beta1 is cell density-dependent and involves down regulation of PDGF alpha-receptors. (C) 1993 Wiley-Liss, Inc.