Transforming growth factor-p (TGF-p) acts as a growth inhibitor, yet it can stimulate proliferation; l-2 fg/cell of TGF-pl 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-p induces a similar response in human fibroblasts and chondrocytes. The amount of TGF-pl per cell that induces maximal proliferation is identical for dense and sparse SMCs. At low concentrations of TGF-p, there is a lo-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-pl decreases transcripts and expression of PDGF receptor a subunits. Hence, TGF-p induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGFAA secretion, which at higher concentrations of lGF-p, is decreased by down-regulation of PDGF receptor a subunits and perhaps by direct growth inhibition.