Vitamin D inhibition of pro-fibrotic effects of transforming growth factor beta1 in lung fibroblasts and epithelial cells.
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 beta1 (TGFbeta1), considered a driver of many fibrotic disorders, we found that 1,25(OH)(2)D(3) inhibited TGFbeta1-induced fibroblast proliferation in a dose-dependent fashion. 1,25(OH)(2)D(3) also inhibited TGFbeta1 stimulation of alpha-smooth muscle actin expression and polymerization and prevented the upregulation of fibronectin and collagen in TGFbeta1-treated fibroblasts. Finally, we examined how 1,25(OH)(2)D(3) affects epithelial-mesenchymal transformation of lung epithelial cells upon exposure to TGFbeta1. We showed that the TGFbeta1-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 TGFbeta1 stimulation, 1,25(OH)(2)D(3) inhibits the pro-fibrotic phenotype of lung fibroblasts and epithelial cells.
Ramirez
Allan M
AM
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, USA. amramir@emory.edu <amramir@emory.edu>
Wongtrakool
Cherry
C
Welch
Teresa
T
Steinmeyer
Andreas
A
Zügel
Ulrich
U
Roman
Jesse
J
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007633:Keratins / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D014807:Vitamin D / Q000494:pharmacology*; D030181:Vitamin D Response Element / Q000235:genetics; D062826:Zonula Occludens-1 Protein
D000199:Actins; D015820:Cadherins; D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D008565:Membrane Proteins; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D018809:Proliferating Cell Nuclear Antigen; D018167:Receptors, Calcitriol; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D053773:Transforming Growth Factor beta1; D062826:Zonula Occludens-1 Protein; D014807:Vitamin D; D007633:Keratins; D002117:Calcitriol