Fadeel B, Ahlin A, Henter J I, Orrenius S, Hampton M B
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden.
Blood. 1998 Dec 15;92(12):4808-18.
Human neutrophils have a short half-life and are believed to die by apoptosis or programmed cell death both in vivo and in vitro. We found that caspases are activated in a time-dependent manner in neutrophils undergoing spontaneous apoptosis, concomitant with other characteristic features of apoptotic cell death such as morphologic changes, phosphatidylserine (PS) exposure, and DNA fragmentation. The treatment of neutrophils with agonistic anti-Fas monoclonal antibodies (MoAbs) significantly accelerated this process. However, in cells treated with the potent neutrophil activator phorbol 12-myristate 13-acetate (PMA), caspase activity was only evident after pharmacologic inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Similarily, inhibition of the NADPH oxidase in constitutive and Fas/APO-1-triggered apoptosis resulted in increased rather than suppressed levels of caspase activity, suggesting that reactive oxygen species may prevent caspases from functioning optimally in these cells. Moreover, oxidants generated via the NADPH oxidase were essential for PS exposure during PMA-induced cell death, but not for neutrophils undergoing spontaneous apoptosis. We conclude that caspases are an important component of constitutive and Fas/APO-1-triggered neutrophil apoptosis. However, these redox sensitive enzymes are suppressed in activated neutrophils, and an alternate oxidant-dependent pathway is used to mediate PS exposure and neutrophil clearance under these conditions.
人类中性粒细胞半衰期较短，据信在体内和体外均通过凋亡或程序性细胞死亡方式死亡。我们发现，在经历自发凋亡的中性粒细胞中，半胱天冬酶以时间依赖性方式被激活，同时伴有凋亡细胞死亡的其他特征，如形态变化、磷脂酰丝氨酸（PS）暴露和DNA片段化。用抗Fas单克隆抗体（MoAb）激动剂处理中性粒细胞可显著加速这一过程。然而，在用强效中性粒细胞激活剂佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）处理的细胞中，只有在对烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶进行药理抑制后，半胱天冬酶活性才明显。同样，在组成性和Fas/APO-1触发的凋亡中抑制NADPH氧化酶导致半胱天冬酶活性水平升高而非受到抑制，这表明活性氧可能会阻止半胱天冬酶在这些细胞中发挥最佳功能。此外，通过NADPH氧化酶产生的氧化剂对于PMA诱导的细胞死亡过程中的PS暴露至关重要，但对于经历自发凋亡的中性粒细胞则并非如此。我们得出结论，半胱天冬酶是组成性和Fas/APO-1触发的中性粒细胞凋亡的重要组成部分。然而，这些对氧化还原敏感的酶在活化的中性粒细胞中受到抑制，在这些条件下会使用另一种依赖氧化剂的途径来介导PS暴露和中性粒细胞清除。
