Vitamin D3 regulation of transforming growth factor-beta system in epithelial and fibroblastic cells--relationships to plasminogen activation.

Vitamin D3 and its analogs are potent regulators of growth and differentiation of various cell types. A mechanism of action of vitamin D3 and other steroid hormones is to enhance the secretion of transforming growth factor-beta (TGF-beta) in target cells. In epidermal keratinocytes, vitamin D3 induced the expression of both TGF-beta 1 and TGF-beta 2 with minor changes in mRNA levels, while in BT-20 breast carcinoma cells the increase in TGF-beta activity was preceded by an induction of mRNA. In both cell systems, the absolute amounts of active TGF-beta increased, and in keratinocytes the proportion of active TGF-beta was also enhanced. A concomitant enhancement of secretion of the latent TGF-beta-binding protein by vitamin D3 was observed in BT-20 cells. Retinoic acid, which is known to interfere with vitamin D3 signaling, slightly decreased the levels of secreted TGF-beta 1 protein in BT-20 cells, but did not significantly affect the vitamin D3-induced increase. In addition to regulation of the TGF-beta system, vitamin D3 decreases pericellular plasminogen activator activity in keratinocytes. Plasmin-mediated proteolytic events are involved in the release from pericellular space and activation of TGF-beta. We analyzed vitamin D3 regulation of fibroblast growth and the secretion of PA activity. Vitamin D3 inhibited fibroblast growth in a concentration-dependent manner and downregulated plasminogen activator activity as in keratinocytes. In fibroblasts, vitamin D3 did not induce notable alterations in TGF-beta 1 or latent TGF-beta-binding protein secretion, suggesting divergent growth inhibitory mechanisms. Our results indicate that vitamin D3 and its analogs are potent regulators of the TGF-beta and plasminogen activator systems in cells of epithelial and mesenchymal origin.