Watson R W, Rotstein O D, Nathens A B, Parodo J, Marshall J C
Department of Surgery, The Toronto Hospital, University of Toronto, Canada.
J Immunol. 1997 Jan 15;158(2):945-53.
Termination of a neutrophil-mediated inflammatory response occurs through the activation of the endogenous cell death program, apoptosis. Neutrophil apoptosis is a constitutive process that can be accelerated or delayed by signals from the microenvironment. Since cellular localization at the site of an inflammatory challenge is the critical first step in a neutrophil response, we investigated the effects of neutrophil transendothelial transmigration on the kinetic expression of apoptosis. Neutrophils isolated from rat lung following challenge with LPS demonstrated a significant delay in spontaneous apoptosis. This delay was a consequence of transmigration, since a comparable delay was seen when TNF-alpha, a potent inducer of apoptosis in vitro, was used as the inflammatory stimulus. Human neutrophils demonstrated comparable delays in apoptosis in vitro following migration across an endothelial monolayer in response to FMLP. Delayed apoptosis only occurred in cells that had first been primed by LPS, a stimulus shown to up-regulate beta2 integrins and down-regulate L-selectin. Finally, crosslinking of CD11a or CD11b, but not of CD18, with mAbs and F(ab')2 fragments produced a delay in spontaneous apoptosis, whereas crosslinking of L-selectin with mAb or its natural ligand, sulfatides, accelerated the apoptotic process. Cells in which apoptosis was inhibited demonstrated persistent functional respiratory burst activity. These observations establish a role for endothelial transmigration in the regulation of neutrophil apoptosis, and suggest that adhesion molecules serve a modulatory role in the expression of neutrophil programmed cell death.
中性粒细胞介导的炎症反应通过内源性细胞死亡程序（即凋亡）的激活而终止。中性粒细胞凋亡是一个组成性过程，可被来自微环境的信号加速或延迟。由于在炎症刺激部位的细胞定位是中性粒细胞反应的关键第一步，我们研究了中性粒细胞跨内皮迁移对凋亡动力学表达的影响。用脂多糖刺激大鼠肺后分离出的中性粒细胞显示出自发性凋亡明显延迟。这种延迟是迁移的结果，因为当体外凋亡的强效诱导剂肿瘤坏死因子-α用作炎症刺激时，也出现了类似的延迟。人中性粒细胞在体外对甲酰甲硫氨酰-亮氨酰-苯丙氨酸（FMLP）作出反应并穿过内皮单层迁移后，凋亡也出现了类似的延迟。延迟凋亡仅发生在最初已被脂多糖致敏的细胞中，脂多糖是一种能上调β2整合素并下调L-选择素的刺激物。最后，用单克隆抗体和F(ab')2片段交联CD11a或CD11b（而非CD18）会导致自发性凋亡延迟，而用单克隆抗体或其天然配体硫脂交联L-选择素则会加速凋亡过程。凋亡受到抑制的细胞表现出持续的功能性呼吸爆发活性。这些观察结果确立了内皮迁移在中性粒细胞凋亡调节中的作用，并表明黏附分子在中性粒细胞程序性细胞死亡的表达中起调节作用。
