TGF-beta 3 stimulates and regulates collagen synthesis through TGF-beta 1-dependent and independent

In contrast to the TGF-beta 1 and beta 2 isoforms, TGF-beta 3 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-beta 3 on cultures of human dermal fibroblasts. TGF-beta 3 (0.1 to 100 pg 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 5 ng per ml, p < 0.001, r = 0.990), and increased alpha 1(I) procollagen mRNA levels (r = 0.999), with maximal effects (200% of control) observed by 24 h, Collagen. lattice contraction was increased by more than 50% in response to TGF-beta 3 (p < 0.001), and to a similar extent as the TGF-beta 1 isoform, Stimulation of collagen synthesis and of alpha 1(I) procollagen mRNA levels in response to TGF-beta 3 was partially blocked by a TGF-beta 1-specific anti-sense oligonucleotide but was still detectable (35% greater than baseline) when TGF-beta 3 was added to dermal fibroblasts from TGF-beta 1 knock-out mice. In contrast with these stimulatory effects,, however, downregulation of alpha 1(I) procollagen, alpha 1(III) procollagen, and TGF-beta 1 mRNA levels toward baseline occurred when TGF-beta 3 (0.1 to 5 ng per ml) was added simultaneously and in combination with TGF-beta 1. We conclude that stimulation of collagen synthesis by TGF-beta 3 occurs through TGF-beta 1-dependent and independent pathways, By downregulating the response to TGF-beta 1, and by shifting from one pathway to the other, TGF-beta 3 can dampen and provide fine-tuning to the overall TGF-beta's induced program of collagen deposition.