Vitamin D inhibition of pro-fibrotic effects of transforming growth factor β1 in lung fibroblasts and epithelial cells

Abstract The mechanisms that control fibroproliferation and matrix deposition in lung fibrosis remain unclear. We speculate that vitamin D deficiency may contribute to pulmonary fibrosis since vitamin D deficiency has been implicated in several diseases. First, we confirmed the presence of vitamin D receptors (VDRs) in cultured NIH/3T3 and lung fibroblasts. Fibroblasts transfected with a vitamin D response element–reporter construct and exposed to the active vitamin D metabolite, 1,25(OH) 2 D 3 , showed increased promoter activity indicating VDR functionality in these cells. Testing the effects of 1,25(OH) 2 D 3 on fibroblasts treated with transforming growth factor β1 (TGFβ1), considered a driver of many fibrotic disorders, we found that 1,25(OH) 2 D 3 inhibited TGFβ1-induced fibroblast proliferation in a dose-dependent fashion. 1,25(OH) 2 D 3 also inhibited TGFβ1 stimulation of α-smooth muscle actin expression and polymerization and prevented the upregulation of fibronectin and collagen in TGFβ1-treated fibroblasts. Finally, we examined how 1,25(OH) 2 D 3 affects epithelial–mesenchymal transformation of lung epithelial cells upon exposure to TGFβ1. We showed that the TGFβ1-induced upregulation of mesenchymal cell markers and abnormal expression of epithelial cell markers were blunted by 1,25(OH) 2 D 3 . These observations suggest that under TGFβ1 stimulation, 1,25(OH) 2 D 3 inhibits the pro-fibrotic phenotype of lung fibroblasts and epithelial cells.