TGF-β1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells
TGF-β1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells
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DOI：
10.4049/jimmunol.168.12.6470
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发表时间：
2002-06-15
影响因子：
4.4
通讯作者：
Hara, N
中科院分区：
文献类型：
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作者：
Hagimoto, N;Kuwano, K;Hara, N
转化生长因子-β 1（TGF-β 1）在肺纤维化中具有重要作用，并有可能诱导几种类型细胞的凋亡。我们先前证实Fas连接诱导的肺上皮细胞凋亡可能参与肺纤维化的发展。在这项研究中，我们表明TGF-β 1通过激活caspase-3和下调细胞周期蛋白依赖性激酶抑制剂p21诱导原代培养的细支气管上皮细胞凋亡。不足以单独诱导凋亡的TGF-β 1浓度可增强激动性抗Fas抗体或rFas配体介导的培养细支气管上皮细胞凋亡。特发性肺纤维化（IPF）患者支气管肺泡灌洗液（BALF）中的可溶性Fas配体也可诱导培养的细支气管上皮细胞凋亡，抗TGF-β Ab可显著减弱凋亡。另外，过敏性肺炎（HP）患者的BALF不能诱导细支气管上皮细胞凋亡，尽管其可溶性Fas配体的量相当。IPF患者BALF中TGF-β 1的浓度显著高于HP患者或对照者。此外，与低浓度的TGF-β 1和HP BALF共孵育产生了与IPF BALF相当的促凋亡作用。在体内，TGF-β 1可通过激活caspase-3增强Fas介导的上皮细胞凋亡和肺损伤。我们的研究结果表明，TGF-β 1作为Fas介导的肺上皮细胞凋亡的增强剂，在肺纤维化的病理生理学中具有新的作用。
Transforming growth factor-beta1 (TGF-beta1) has important roles in lung fibrosis and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary fibrosis. In this study, we show that TGF-beta1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. Concentrations of TGF-beta1 that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or rFas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis (HP) could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble Fas ligand. The concentrations of TGF-beta1 in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of TGF-beta1 and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of TGF-beta1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-beta1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.