Transforming growth factor beta 1 downregulates the platelet-derived growth factor alpha-receptor subtype on human lung fibroblasts in vitro

Am J Respir Cell Mol Biol. 1995 Oct;13(4):496-505. doi: 10.1165/ajrcmb.13.4.7546780.


Fibroblasts are the central target cell in pulmonary fibrotic diseases, and their proliferation is mediated largely by platelet-derived growth factor (PDGF) isoforms secreted by activated lung macrophages. Several other macrophage-derived cytokines that are increased during fibrogenesis, including interleukin-1 beta and transforming growth factor-beta 1 (TGF-beta 1), could potentially modulate the mitogenic and chemotactic activity of PDGF by altering the expression of cell-surface PDGF receptors on fibroblasts. The PDGF receptor system on fibroblasts from a variety of tissues shows heterogeneous responses to TGF-beta 1. Lung fibroblasts have not been investigated in this regard. TGF-beta 1 downregulated the gene expression of the 6.5 kb PDGF-alpha receptor (PDGF-R alpha) transcript in normal human lung fibroblasts in a concentration-dependent fashion that was maximal at 3 ng/ml TGF-beta 1; this corresponded with a decrease in cell-surface PDGF-R alpha as measured by radioligand binding assays using [125I]PDGF-AA. The TGF-beta 1-induced down-regulation of the PDGF-R alpha gene was rapid (maximal suppression by 2 h post-treatment) and preceded the decrease in cell-surface alpha-receptor (maximal reduction by 6 h post-treatment). TGF-beta 1 treatment did not alter the rate of PDGF-R alpha mRNA degradation following the inhibition of transcription using actinomycin D, indicating that TGF-beta 1 increases PDGF-R alpha transcription. Scatchard analysis of saturation binding data showed that TGF-beta 1 decreased the number of [125I]PDGF-AA binding sites 5-fold without affecting receptor affinity. [125I]PDGF-AB binding sites were downregulated approximately 25%, and the number of [125I]PDGF-BB binding sites was not changed by TGF-beta 1 treatment, indicating that the PDGF-beta receptor was not affected. TGF-beta 1 reduced the mitogenic and chemotactic response to PDGF-AA by > 90%, whereas these biologic response to PDGF-AB and PDGF-BB were inhibited 50% to 80%. The proliferative and chemotactic responses of fibroblasts during tissue remodeling or during lung fibrosis are likely controlled by a complex network involving PDGF isoforms and cytokines that modify the PDGF receptor system.

MeSH terms

  • Becaplermin
  • Cells, Cultured
  • Chemotaxis / drug effects
  • DNA / biosynthesis
  • Dactinomycin / pharmacology
  • Down-Regulation / drug effects*
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Kinetics
  • Lung
  • Mitogens / pharmacology
  • Platelet-Derived Growth Factor / metabolism
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Platelet-Derived Growth Factor / biosynthesis*
  • Receptors, Platelet-Derived Growth Factor / genetics
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Transcription, Genetic / drug effects
  • Transforming Growth Factor beta / pharmacology*


  • Mitogens
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger
  • Transforming Growth Factor beta
  • platelet-derived growth factor A
  • platelet-derived growth factor AB
  • Becaplermin
  • Dactinomycin
  • Epidermal Growth Factor
  • DNA
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Platelet-Derived Growth Factor