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-beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 on PDGF-AA-induced mitogenesis was density-dependent; when dense cell cultures were preincubated with TGF-beta 1, there was an complete inhibition of 3H-thymidine incorporation, whereas the effect was less in sparse cultures. A similar density-dependent effect of TGF-beta 1 was seen in PDGF-BB treated cells, although less pronounced. The binding of 125I-labeled PDGF-AA and PDGF-BB to the alpha-receptor was significantly reduced after treatment with TGF-beta 1 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-beta 1 is cell density-dependent and involves down-regulation of PDGF alpha-receptors.
Paulsson
Y
Y
Department of Pathology, University Hospital, Uppsala, Sweden.
Karlsson
C
C
Heldin
C H
CH
Westermark
B
B
D002452:Cell Count / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D010982:Platelet-Derived Growth Factor / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D013936:Thymidine