TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
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DOI：
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发表时间：
2002
影响因子：
4.4
通讯作者：
N. Hagimoto;K. Kuwano;Ichiro Inoshima;M. Yoshimi;N. Nakamura;M. Fujita;T. Maeyama;N. Hara
中科院分区：
文献类型：
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作者：
N. Hagimoto;K. Kuwano;Ichiro Inoshima;M. Yoshimi;N. Nakamura;M. Fujita;T. Maeyama;N. Hara
转化生长因子-β 1 (TGF-β 1) 在肺纤维化中发挥重要作用，并有可能诱导多种细胞凋亡。我们之前证明Fas连接诱导的肺上皮细胞凋亡可能参与肺纤维化的发生。在这项研究中，我们发现 TGF-β1 通过激活 caspase-3 和下调细胞周期蛋白依赖性激酶抑制剂 p21 来诱导原代培养的细支气管上皮细胞凋亡。单独不足以诱导细胞凋亡的 TGF-β 1 浓度可以增强激动性抗 Fas Ab 或 rFas 配体介导的培养细支气管上皮细胞的细胞凋亡。特发性肺纤维化 (IPF) 患者的支气管肺泡灌洗液 (BALF) 中的可溶性 Fas 配体也诱导培养的细支气管上皮细胞凋亡，抗 TGF-β Ab 显着减弱这种凋亡作用。另外，来自过敏性肺炎（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-β1 的浓度显着高于 HP 患者或对照患者 BALF 中的浓度。此外，与低浓度的 TGF-β1 和 HP BALF 共孵育产生了与 IPF BALF 相当的促凋亡作用。在体内，给予小鼠 TGF-β1 可以通过激活 caspase-3 来增强 Fas 介导的上皮细胞凋亡和肺损伤。我们的结果证明了 TGF-β1 作为 Fas 介导的肺上皮细胞凋亡增强剂在肺纤维化病理生理学中的新作用。
Transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 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-beta 1 and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of TGF-beta 1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-beta 1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.