Youker K, Smith C W, Anderson D C, Miller D, Michael L H, Rossen R D, Entman M L
Department of Medicine, Methodist Hospital, Houston, Texas.
J Clin Invest. 1992 Feb;89(2):602-9. doi: 10.1172/JCI115626.
Canine neutrophils can be induced to adhere in vitro to isolated adult cardiac myocytes by stimulation of the neutrophils with chemotactic factors such as zymosan-activated serum (ZAS) only if the myocytes have been previously exposed to cytokines such as interleukin 1 (IL-1) or tumor necrosis factor-alpha. These cytokines induce synthesis and surface expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte, and neutrophil adhesion is almost entirely CD18 and ICAM-1 dependent. The present study examines cardiac-specific lymph collected from awake dogs during 1-h coronary occlusion and 3 d of reperfusion for its ability to induce both ICAM-1 expression in cardiac myocytes, and neutrophil-myocyte adherence. Reperfusion lymph induced ICAM-1 expression in isolated myocytes, and myocyte adherence to ZAS-stimulated neutrophils that was completely inhibited by anti-CD18 and anti-ICAM-1 monoclonal antibodies. This activity peaked at 90 min of reperfusion and persisted for up to 72 h. Preischemic lymph was not stimulatory. IL-1 appeared not to be a stimulating factor in lymph in that dilutions of lymph were found to inhibit the stimulatory effects of recombinant IL-1 beta. However, investigation of interleukin 6 (IL-6) revealed that recombinant IL-6 stimulated myocyte adhesiveness for ZAS-stimulated neutrophils (ED50 = 0.002 U/ml) and expression of ICAM-1 by isolated myocytes. IL-6 neutralizing antibody markedly reduced the ability of reperfusion lymph to stimulate adhesion and ICAM-1 expression, and estimates of levels of IL-6 in reperfusion lymph ranged from 0.035 to 0.14 U/ml. These results indicate that cytokines capable of promoting neutrophil-myocyte adhesion occur in extracellular fluid during reperfusion of ischemic myocardium, and that one of these cytokines is IL-6. Neutrophil-myocyte adhesion may be of pathogenic significance because it may enhance the cytotoxic activity of the neutrophil.
只有当成年心肌细胞预先暴露于诸如白细胞介素1（IL-1）或肿瘤坏死因子-α等细胞因子时，通过用趋化因子（如酵母聚糖激活血清，ZAS）刺激中性粒细胞，犬中性粒细胞才能在体外诱导黏附于分离的成年心肌细胞。这些细胞因子诱导心肌细胞上细胞间黏附分子-1（ICAM-1）的合成和表面表达，并且中性粒细胞黏附几乎完全依赖于CD18和ICAM-1。本研究检测了清醒犬在1小时冠状动脉闭塞和3天再灌注期间收集的心脏特异性淋巴液，以评估其诱导心肌细胞中ICAM-1表达以及中性粒细胞与心肌细胞黏附的能力。再灌注淋巴液可诱导分离的心肌细胞中ICAM-1的表达，以及心肌细胞与ZAS刺激的中性粒细胞的黏附，而抗CD18和抗ICAM-1单克隆抗体可完全抑制这种黏附。这种活性在再灌注90分钟时达到峰值，并持续长达72小时。缺血前淋巴液无刺激作用。IL-1似乎不是淋巴液中的刺激因子，因为发现淋巴液的稀释液可抑制重组IL-1β的刺激作用。然而，对白细胞介素6（IL-6）的研究表明，重组IL-6可刺激心肌细胞对ZAS刺激的中性粒细胞的黏附性（半数有效剂量=0.002 U/ml）以及分离的心肌细胞中ICAM-1的表达。IL-6中和抗体显著降低了再灌注淋巴液刺激黏附及ICAM-1表达的能力，再灌注淋巴液中IL-6水平的估计值在0.035至0.14 U/ml之间。这些结果表明，在缺血心肌再灌注期间，细胞外液中存在能够促进中性粒细胞与心肌细胞黏附的细胞因子，其中一种细胞因子就是IL-6。中性粒细胞与心肌细胞的黏附可能具有致病意义，因为它可能增强中性粒细胞的细胞毒性活性。
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