Nakagawa K, Miller F N, Sims D E, Lentsch A B, Miyazaki M, Edwards M J
Department of Surgery, University of Louisville, Kentucky 40292, USA.
Cancer Res. 1996 Feb 1;56(3):507-10.
Interleukin 2 (IL-2) mediates the regression of metastatic cancer, but its clinical use is limited by associated toxicities including hepatic dysfunction. To determine the mechanism for IL-2-induced hepatic dysfunction, we hypothesized that IL-2 activation of Kupffer cells causes leukocyte-endothelial adhesion and decreases hepatic sinusoidal blood flow. C57BL/6 mice were given injections of latex particles and prepared for intravital hepatic microscopy 2 h after i.p. IL-2 administration. Liver tissue was also prepared to quantitate hepatic tumor necrosis factor (TNF) mRNA and processed for light and electron microscopy. Phagocytosing Kupffer cells and leukocytes adherent to the endothelium were counted, and surface sinusoidal blood flow was quantitated. Kupffer cell activity was quantitated as the ratio of phagocytosing Kupffer cells to sinusoidal blood flow. IL-2 significantly increased Kupffer cell activity (0.56 +/- 0.05 for controls versus 0.84 +/- 0.05 for IL-2), significantly caused leukocyte-endothelial adhesion (26.7 +/- 7.9 for controls versus 87.0 +/- 27.6 for IL-2, WBC/mm2 endothelial surface), and significantly decreased the number of sinusoids containing blood flow per microscopic field (6.66 +/- 0.15 for controls versus 5.79 +/- 0.13 for IL-2) without causing changes in systemic hemodynamic parameters. In IL-2 treated livers, light and electron microscopy showed the constriction of sinusoids associated with swollen or ruptured mitochondria, which was consistent with hypoxic deterioration near central venules. Adherent platelets, neutrophils, and lymphocytes within sinusoids and central venules were also observed. PCR revealed that IL-2 significantly induced TNF mRNA expression in the liver. These data suggest that IL-2 activates Kupffer cells in association with the release of monokines including TNF, which causes activation of circulating leukocytes as well as hepatic sinusoidal endothelial cells. The resultant leukocyte and platelet adhesion to the endothelium may then physically impede the sinusoidal microcirculation, resulting in microscopic areas of hepatic ischemia and explaining the mechanism of IL-2-induced hepatic dysfunction.
白细胞介素2（IL-2）介导转移性癌症的消退，但其临床应用受到包括肝功能障碍在内的相关毒性的限制。为了确定IL-2诱导肝功能障碍的机制，我们推测IL-2激活库普弗细胞会导致白细胞与内皮细胞黏附，并减少肝血窦血流量。给C57BL/6小鼠腹腔注射乳胶颗粒，并在腹腔注射IL-2后2小时准备进行肝活体显微镜检查。还制备了肝组织以定量肝肿瘤坏死因子（TNF）mRNA，并进行光镜和电镜检查。对吞噬性库普弗细胞和黏附在内皮细胞上的白细胞进行计数，并定量表面血窦血流量。将库普弗细胞活性定量为吞噬性库普弗细胞与血窦血流量的比值。IL-2显著增加了库普弗细胞活性（对照组为0.56±0.05，IL-2组为0.84±0.05），显著导致白细胞与内皮细胞黏附（对照组为2,67±7.9，IL-2组为87.0±27.6，白细胞/mm²内皮细胞表面），并且显著减少每个显微镜视野中含有血流的血窦数量（对照组为6.66±0.15，IL-2组为5.79±0.13），而未引起全身血流动力学参数的变化。在接受IL-2治疗的肝脏中，光镜和电镜检查显示血窦收缩，伴有线粒体肿胀或破裂，这与中央静脉附近的缺氧恶化一致。还观察到血窦和中央静脉内有黏附的血小板、中性粒细胞和淋巴细胞。聚合酶链反应显示IL-2显著诱导肝脏中TNF mRNA表达。这些数据表明，IL-2激活库普弗细胞并伴有包括TNF在内的单核因子释放，这会导致循环白细胞以及肝血窦内皮细胞激活。随后，白细胞和血小板与内皮细胞的黏附可能会在物理上阻碍血窦微循环，导致肝脏局部缺血，从而解释了IL-2诱导肝功能障碍的机制。
