Alpha-defensins increase lung fibroblast proliferation and collagen synthesis via the beta-catenin signaling pathway.
Alpha-defensins increase lung fibroblast proliferation and collagen synthesis via the beta-catenin signaling pathway.
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DOI：
10.1111/j.1742-4658.2009.07370.x
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Su Y
中科院分区：
文献类型：
--
作者：
Han W;Wang W;Mohammed KA;Su Y
α-防御素是从白细胞颗粒中释放出来的，与炎症性和纤维性肺部疾病有关。本研究观察了α-防御素对肺成纤维细胞增殖和胶原合成的影响。我们发现α-防御素-1和α-防御素-2呈剂量依赖性地诱导两株人肺成纤维细胞(HFL-1和LL-86)新合成的5-溴-2‘-脱氧尿苷掺入，提示α-防御素-1和α-防御素-2刺激肺成纤维细胞的增殖。α-防御素-1和α-防御素-2也可增加肺成纤维细胞(HFL-1和LL-86)I型胶原和活性/去磷酸化β-连环蛋白的水平和蛋白含量，但不改变β-连环蛋白的总含量。用栎素抑制β-连环蛋白信号通路可阻止肺成纤维细胞增殖、β-I和活性/去磷酸化α-连环蛋白蛋白含量的增加，以及α-防御素-1和COL1A1-2诱导的COL1A1mRNA水平和胶原释放增加。用小干扰核糖核酸技术敲除β-连环蛋白还可阻止α-防御素诱导的细胞增殖和肺成纤维细胞中I型胶原和活性/去磷酸化β-连环蛋白的蛋白含量以及COL1A1mRNA水平的增加。此外，p38丝裂原活化蛋白激酶抑制剂SB203580和磷脂酰肌醇3-激酶抑制剂LY294002可抑制糖原合成酶3β的磷酸化、β-连环蛋白的积聚/激活以及α-防御素-1和α-防御素-2诱导的胶原合成增加。这些结果表明，α-防御素-1和α-防御素-2促进肺成纤维细胞的增殖和胶原合成。β-连环蛋白信号通路介导α-防御素诱导的肺成纤维细胞增殖和胶原合成增加。α防御素诱导肺成纤维细胞β-连环蛋白的激活可能是通过激活p38丝裂原活化蛋白激酶和磷脂酰肌醇3-激酶/AKT信号通路导致糖原合成酶3β的磷酸化/失活所致。
α-defensins are released from granules of leukocytes and are implicated in inflammatory and fibrotic lung diseases. In the present study, the effects of α-defensins on the proliferation and collagen synthesis of lung fibroblasts were examined. We found that α-defensin-1 and α-defensin-2 induced dose-dependent increases in the incorporation of 5-bromo-2′-deoxy-uridine into newly synthesized DNA in two lines of human lung fibroblasts (HFL-1 and LL-86), suggesting that α-defensin-1 and α-defensin-2 stimulate the proliferation of lung fibroblasts. α-defensin-1 and α-defensin-2 also increased collagen-I mRNA (COL1A1) levels and protein contents of collagen-I and active/dephosphorylated β-catenin without changes in total β-catenin protein content in lung fibroblasts (HFL-1 and LL-86). Inhibition of the β-catenin signaling pathway using quercetin prevented increases in cell proliferation and the protein content of collagen-I and active/dephosphorylated β-catenin in lung fibroblasts, and in COL1A1 mRNA levels and collagen release into culture medium induced by α-defensin-1 and α-defensin-2. Knocking-down β-catenin using small interfering RNA technology also prevented α-defensin-induced increases in cell proliferation and the protein content of collagen-I and active/dephosphorylated β-catenin in lung fibroblasts, and in COL1A1 mRNA levels. Moreover, increases in the phosphorylation of glycogen synthase kinase 3β, accumulation/activation of β-catenin, and collagen synthesis induced by α-defensin-1 and α-defensin-2 were prevented by p38 mitogen-activated protein kinase inhibitor SB203580 and phosphoinositide 3-kinase inhibitor LY294002. These results indicate that α-defensin-1 and α-defensin-2 stimulate proliferation and collagen synthesis of lung fibroblasts. The β-catenin signaling pathway mediates α-defensin-induced increases in cell proliferation and collagen synthesis of lung fibroblasts. α-defensin-induced activation of β-catenin in lung fibroblasts might be caused by phosphorylation/inactivation of glycogen synthase kinase 3β as a result of the activation of the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways.
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作者：
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DOI：
10.1016/j.jcf.2003.12.008
发表时间：
2004-03-01
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
--
作者：
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通讯作者：
Bals, Robert