Fujita Tadashi, Maruyama Muneharu, Araya Jun, Sassa Kazuhiko, Kawagishi Yukio, Hayashi Ryuji, Matsui Shoko, Kashii Tatsuhiko, Yamashita Naohiro, Sugiyama Eiji, Kobayashi Masashi
The First Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Japan.
Am J Respir Cell Mol Biol. 2002 Nov;27(5):542-52. doi: 10.1165/rcmb.4775.
Fas mediates apoptosis following binding with Fas ligand. Fas is expressed in human airway epithelial cells and has a critical role in the pathophysiology of various pulmonary disorders. Hydrogen peroxide (H(2)O(2)) is an important mediator of airway epithelial injury. In this context, we hypothesized that H(2)O(2) would increase the expression of cell surface Fas in human airway epithelial cells. To test this hypothesis, the modulation of Fas expression with H(2)O(2) was assessed in normal human bronchial epithelial cells and A549 cells. The majority of Fas was cytoplasmic in both cell types without any stimulation. Hydrogen peroxide significantly increased Fas in the plasma membrane fraction, while decreasing Fas in the cytoplasmic fraction. Incubation with an agonistic antibody for Fas induced apoptosis in H(2)O(2)-treated cells in proportion to the level of surface Fas expression on those cells. Inhibitors of poly(ADP-ribose) polymerase abrogated the H(2)O(2)-induced Fas translocation to the plasma membrane and p53 activation. Expression of dominant-negative p53 also inhibited the Fas translocation induced by H(2)O(2) in A549 cells. These results indicate that H(2)O(2) induces Fas upregulation by promoting cytoplasmic transport of Fas to the cell surface in human airway epithelial cells, and that the activation of the poly(ADP-ribose) polymerase-p53 pathway may be involved in this mechanism.
Fas与Fas配体结合后介导细胞凋亡。Fas在人呼吸道上皮细胞中表达，在各种肺部疾病的病理生理学中起关键作用。过氧化氢（H₂O₂）是呼吸道上皮损伤的重要介质。在此背景下，我们假设H₂O₂会增加人呼吸道上皮细胞表面Fas的表达。为了验证这一假设，我们在正常人支气管上皮细胞和A549细胞中评估了H₂O₂对Fas表达的调节作用。在未受任何刺激的情况下，两种细胞类型中的大多数Fas都位于细胞质中。过氧化氢显著增加了质膜部分的Fas，同时减少了细胞质部分的Fas。用Fas激动性抗体孵育可诱导H₂O₂处理的细胞发生凋亡，其凋亡程度与这些细胞表面Fas表达水平成正比。聚（ADP-核糖）聚合酶抑制剂消除了H₂O₂诱导的Fas向质膜的转位和p53激活。显性负性p53的表达也抑制了H₂O₂在A549细胞中诱导的Fas转位。这些结果表明，H₂O₂通过促进Fas在人呼吸道上皮细胞中从细胞质向细胞表面的转运来诱导Fas上调，并且聚（ADP-核糖）聚合酶-p53途径的激活可能参与了这一机制。
