Abstract
In contrast to the TGF-β1 and β2 isoforms, TGF-β3 has shown the ability to downregulate scarring and fibrosis in vivo under certain experimental conditions. In this study, we determined the direct effects of TGF-β3 on cultures of human dermal fibroblasts. TGF-β3 (0.1 to 100pg per ml) increased DNA synthesis up to 50% (p<0.01, r 0.970), collagen protein synthesis up to 200% (dose range of 0.1 to 5ng per ml, p<0.001, r=0.990), and increased α1(I) procollagen mRNA levels (r=0.999), with maximal effects (200% of control) observed by 24h. Collagen lattice contraction was increased by more than 50% in response to TGF-β3 (p<0.001), and to a similar extent as the TGF-β1 isoform. Stimulation of collagen synthesis and of α1(I) procollagen mRNA levels in response to TGF-β3 was partially blocked by a TGF-β1-specific anti-sense oligonucleotide but was still detectabIe (35% greater than baseline) when TGF-β3 was added to dermal fibroblasts from TGF-β1 knock-out mice. In contrast with these stimulatory effects, however, downregulation of α1(I) procohagen, α1(III) procollagen, and TGF-β1 mRNA levels toward baseline occurred when TGF-β3 (0.1 to 5ng per ml) was added simultaneously and in combination with TGF-β1. We conclude that stimulation of collagen synthesis by TGF-β3 occurs through TGF-β1-dependent and independent pathways. By downregulating the response to TGF-βl and by shifting from one pathway to the other, TGF-β3 can dampen and provide finetuning to the overall TGF-β's induced program of collagen deposition.
