TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop.
Transforming growth factor-beta (TGF-beta) acts as a growth inhibitor, yet it can stimulate proliferation; 1-2 fg/cell of TGF-beta 1 elicits maximal proliferation of dense and sparse cultured smooth muscle cells (SMCs), whereas higher amounts are less stimulatory. This bimodal response is not limited to SMCs, as TGF-beta induces a similar response in human fibroblasts and chondrocytes. The amount of TGF-beta 1 per cell that induces maximal proliferation is identical for dense and sparse SMCs. At low concentrations of TGF-beta, there is a 10-12 hr delay in DNA synthesis compared with that elicited by PDGF. PDGF-AA is detected in the culture medium at 24 hr, and anti-PDGF IgG blocks DNA synthesis. At higher concentrations, TGF-beta 1 decreases transcripts and expression of PDGF receptor alpha subunits. Hence, TGF-beta induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGF-AA secretion, which at higher concentrations of TGF-beta, is decreased by down-regulation of PDGF receptor alpha subunits and perhaps by direct growth inhibition.
Battegay
E J
EJ
Department of Pathology, University of Washington, Seattle 98195.
Raines
E W
EW
Seifert
R A
RA
Bowen-Pope
D F
DF
Ross
R
R
D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002356:Cartilage / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D046911:Macromolecular Substances; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D046911:Macromolecular Substances; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor