Vitamin D attenuates TGF-β1-induced lung fibroblast proliferation and migration through repression of RasGRP3 |
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| Authors: | GUANQIONG HU RISHENG HUANG LUELUE LU QINSHI PAN XIAOXIN CHEN |
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| Affiliation: | 1.No. 23 Ward of Nursing Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China 2 Department of Thoracic Surgery, Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, Wenzhou, China3 Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China |
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| Abstract: | Background: Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that plays a central role in thepathogenesis of idiopathic pulmonary fibrosis (IPF). While previous studies have revealed a cross-talk between vitamin Dand TGF-β1 signaling, it is still unclear how they interact with each other to regulate the progression of IPF. Methods: Inthis work, we searched for a novel mediator of TGF-β1 activity in lung fibroblasts and examined its regulation by vitaminD. In addition, we investigated the mechanism underlying the interaction between vitamin D and TGF-β1 signaling inlung fibroblast activation. Bioinformatic analysis was performed to identify TGF-β1 downstream target genes.Knockdown and overexpression expression experiments were conducted to determine gene function in the regulationof lung fibroblast proliferation and migration. Results: Analysis of publicly available datasets revealed that RASguanyl releasing protein 3 (RasGRP3) was upregulated in TGF-β1-treated lung fibroblasts and lung tissues from IPFpatients relative to healthy controls. Our data confirmed the upregulation of RasGRP3 by TGF-β1 in human MRC5lung fibroblasts. Overexpression of RasGRP3 enhanced MRC5 cell proliferation and migration. Knockdown ofRasGRP3 blocked TGF-β1-induced MRC5 proliferation and migration. Vitamin D abolished TGF-β1-inducedRasGRP3 upregulation, which was reversed by inhibition of the vitamin D receptor (VDR). Mechanistically, vitaminD promoted VDR enrichment and prevented mothers against decapentaplegic homolog (SMAD) 2 and 3 occupancyat the promoter of RasGRP3. Additionally, overexpression of RasGRP3 reversed the suppressive effect of vitamin Don MRC5 cell proliferation and migration. Conclusion: In conclusion, vitamin D antagonizes TGF-β1-induced lungfibroblast activation by repressing RasGRP3 transcription. |
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| Keywords: | Lung fibrosis RasGRP3 TGF-β1 Vitamin D |
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