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首页> 外文期刊>American Journal of Physiology >TGF-beta1 epigenetically modifies Thy-1 expression in primary lung fibroblasts
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TGF-beta1 epigenetically modifies Thy-1 expression in primary lung fibroblasts

机译：TGF-β1表现出原发性肺成纤维细胞中的THY-1表达

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摘要

Idiopathic pul-monary fibrosis is a progressive lung disease that increases in incidence with age. We identified a profibrotic lung phenotype in aging mice characterized by an increase in the number of fibroblasts lacking the expression of thymocyte differentiation antigen 1 (Thy-1) and an increase in transforming growth factor (TGF)-beta1 expression. It has been shown that Thy-1 expression can be epigenetically modified. Lung fibroblasts (PLFs) were treated with TGF-beta1 ± DNA methyl-transferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-AZA) and analyzed for Thy-1 gene and protein expression, DNMT protein expression, and activity. alpha-Smooth muscle actin (alpha-SMA) and collagen type 1 (CollAl) gene and protein expression was assessed. PLFs were transfected with DNMT1 silencing RNA ± TGF-beta1. TGF-beta1 inhibited Thy-1 gene and protein expression in PLFs, and cotreatment with 5-AZA ameliorated this effect and appeared to inhibit DNMT1 activation. TGF-beta1 induced Thy-1 promoter methylation as assessed by quantitative methyl PCR. Treatment with 5-AZA attenuated TGF-beta1-induced Col1A1 gene and protein expression and alpha-SMA gene expression (but not a-SMA protein expression). Inhibiting DNMT1 with silencing RNA attenuated TGF-beta1-induced DNMT activity and its downstream suppression of Thy-1 mRNA and protein expression as well as inhibited a-SMA mRNA and Col1A1 mRNA and protein expression, and showed a decreased trend in Thy-1 promoter methylation. Immunofluorescence for alpha-SMA suggested that 5-AZA inhibited stress fiber formation. These findings suggest that TGF-beta1 epigenetically regulates lung fibroblast phenotype through methylation of the Thy-1 promoter. Targeted inhibition of DNMT in the right clinical context might prevent fibroblast to myofibroblast transdiffer-entiation and collagen deposition, which in turn could prevent fibro-genesis in the lung and other organs.
机译：特发性润肤型纤维化是一种渐进的肺病，随着年龄的增长而增加。我们鉴定了衰老小鼠中的血压肺表型，其特征在于缺乏抑制胸腺细胞分化抗原1（THY-1）表达的成纤维细胞数量的增加和转化生长因子（TGF）-Beta1表达的增加。已经表明，可以将其表达表达能够进行表现出外观修改。用TGF-β1±DNA甲基转移酶（DNMT）抑制剂5-AZA-2'-脱氧胞苷（5-AZA）处理肺成纤维细胞（PLF），并分析THY-1基因和蛋白表达，DNMT蛋白表达和活性。评估α-平滑肌肌动蛋白（α-SMA）和胶原型1（Collal）基因和蛋白表达。用DNMT1沉默RNA±TGF-BETA1转染PLF。 TGF-β1抑制PLF中的THY-1基因和蛋白质表达，并且用5-AZA改善了这种效果的分配物，并且似乎抑制DNMT1活化。 TGF-β1诱导如定量甲基PCR评估的Thy-1启动子甲基化。用5-AZA衰减的TGF-BETA1诱导的COL1A1基因和蛋白表达和α-SMA基因表达（但不是A-SMA蛋白表达）处理。抑制沉默RNA的DNMT1衰减TGF-BETA1诱导的DNMT活性及其下游抑制THY-1 mRNA和蛋白质表达以及抑制A-SMA mRNA和COL1A1 mRNA和蛋白质表达，并显示出THY-1启动子的趋势降低甲基化。 α-SMA的免疫荧光表明，5-AZA抑制应激纤维形成。这些发现表明，TGF-β1通过Thy-1启动子的甲基化表现出肺成纤维细胞表型。靶向抑制DNMT在右侧临床上下文中可能预防成纤维细胞对肌纤维细胞转化率和胶原沉积，其又可以防止肺和其他器官中的纤维生成。

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