Vidal-Vanaclocha F, Amézaga C, Asumendi A, Kaplanski G, Dinarello C A
Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain.
Cancer Res. 1994 May 15;54(10):2667-72.
Hepatic metastasis in melanoma is affected by processes of tumor cell adhesion to sinusoidal cells, avoidance of cytotoxic cells, and local growth-promoting activity. A role for interleukin-1 (IL-1) in these events was evaluated in vitro and in vivo by specifically blocking IL-1 receptors using the naturally occurring IL-1 receptor antagonist (IL-1Ra). At 10- and 100-fold molar excess, IL-1Ra reduced the IL-1-mediated adhesion of B16 melanoma cells to cultured hepatic sinusoidal endothelial cells by 60 and 100%, respectively. Conditioned media derived from murine hepatic sinusoidal endothelial cells contain growth-promoting activity for B16 cells, and IL-1 increased its production 2.5-fold (P < 0.01). The addition of IL-1Ra to sinusoidal cells reduced the spontaneous release of the growth-promoting activity by 32% (P < 0.05). In addition, blocking IL-1 receptors on melanoma cells reduced their responsiveness to endothelial-conditioned medium (P < 0.05). A single dose of IL-1Ra (0.5 mg/kg) given to mice i.p. 2 h prior to intrasplenic injection of melanoma cells reduced the number of hepatic metastases by 50% and the metastatic volume by 70% compared to vehicle-injected controls (P < 0.01). When given 2, 4, and 6 days after the injection of tumor cells, IL-1Ra reduced the volume of metastases by 58% (P < 0.01). Fifty % of mice pretreated with 0.5 mg/kg IL-1Ra and given 3 additional doses on days 2, 4, and 6 died after 13.5 +/- 0.4 days compared to 11.3 +/- 0.2 days for controls (P < 0.01). In mice pretreated and given 10 daily doses at 5 mg/kg, there was an 80% reduction in hepatic metastases. Using this regimen, survival was 18.1 +/- 2.4 days in the IL-1Ra group and 11.2 +/- 1.5 in controls (P < 0.001). These studies demonstrate a significant role for IL-1 in implantation and growth of metastatic melanoma in the liver.
黑色素瘤的肝转移受肿瘤细胞与窦状细胞黏附、逃避细胞毒性细胞以及局部生长促进活性等过程的影响。通过使用天然存在的白细胞介素-1受体拮抗剂（IL-1Ra）特异性阻断IL-1受体，在体外和体内评估了IL-1在这些事件中的作用。在摩尔过量10倍和100倍时，IL-1Ra分别使B16黑色素瘤细胞与培养的肝窦状内皮细胞的IL-1介导的黏附减少60%和100%。源自小鼠肝窦状内皮细胞的条件培养基含有对B16细胞的生长促进活性，IL-1使其产生增加2.5倍（P < 0.01）。向窦状细胞中添加IL-1Ra可使生长促进活性的自发释放减少32%（P < 0.05）。此外，阻断黑色素瘤细胞上的IL-1受体可降低其对内皮细胞条件培养基的反应性（P < 0.05）。在脾内注射黑色素瘤细胞前2小时腹腔注射给小鼠单剂量IL-1Ra（0.5 mg/kg），与注射赋形剂的对照组相比，肝转移灶数量减少50%，转移体积减少70%（P < 0.01）。在注射肿瘤细胞后2、4和6天给予IL-1Ra，转移灶体积减少58%（P < 0.01）。预先用0.5 mg/kg IL-1Ra处理并在第2、4和6天再给予3剂的小鼠中，50%在13.5±0.4天后死亡，而对照组为11.3±0.2天（P < 0.01）。在预先处理并以5 mg/kg给予10剂每日剂量的小鼠中，肝转移减少80%。采用该方案，IL-1Ra组的生存期为18.1±2.4天，对照组为11.2±1.5天（P < 0.001）。这些研究表明IL-1在肝转移性黑色素瘤的植入和生长中起重要作用。
