Chang M J, Modzelewski R A, Russell D M, Johnson C S
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
Cancer Res. 1996 Feb 15;56(4):886-91.
The role of nitric oxide (NO) in vascular function, host tumoricidal activity, and antiinflammatory effects is well documented. A number of cytokines induce NO from a variety of cell types. We have demonstrated in murine models that interleukin 1 alpha (IL-1 alpha) induces acute hemorrhagic necrosis, microvascular injury, and enhanced clonogenic tumor cell kill. Effects on the vasculature are observed only in tumor and not in normal tissues. Using methods established previously in our laboratory, murine tumor-derived and normal endothelial cells were cultured with IL-1 alpha, IFN-gamma, or IL-1 alpha/IFN-gamma at various doses with NO production quantitated through the measurement of nitrite by the Griess reaction. In tumor-derived endothelial cells, we demonstrated that neither cytokine alone was capable of inducing nitrite but that the combination of IL-1 alpha/IFN-gamma induced dose-dependent nitrite, with peak levels observed after 4 days incubation. When tumor-derived, normal yolk sac, mouse brain, or mouse aortic endothelial cells were treated with IL-1 alpha (100 units/ml)/IFN-gamma (10 units/ml), tumor-derived endothelial cells produced significantly more nitrite when compared to the normal endothelial cells. Nitrite production from IL-1 alpha/IFN-gamma was sensitive to the nitric oxide synthase inhibitors, NG-methyl-L-arginine or NG-nitro-L-arginine in a dose-dependent manner. In addition, dexamethasone significantly inhibited nitrite production from IL-1 alpha/IFN-gamma-treated, tumor-derived endothelial cells. These studies suggest that the antitumor activity of IL-1 alpha may be mediated through the production of NO from tumor-derived endothelial cells.
一氧化氮（NO）在血管功能、宿主肿瘤杀伤活性和抗炎作用中的作用已得到充分证明。许多细胞因子可诱导多种细胞类型产生NO。我们在小鼠模型中已证明，白细胞介素1α（IL-1α）可诱导急性出血性坏死、微血管损伤，并增强肿瘤克隆细胞的杀伤作用。对血管系统的影响仅在肿瘤组织中观察到，而在正常组织中未观察到。使用我们实验室先前建立的方法，将小鼠肿瘤来源的内皮细胞和正常内皮细胞与不同剂量的IL-1α、干扰素-γ（IFN-γ）或IL-1α/IFN-γ一起培养，并通过格里斯反应测量亚硝酸盐来定量NO的产生。在肿瘤来源的内皮细胞中，我们证明单独的细胞因子均不能诱导亚硝酸盐产生，但IL-1α/IFN-γ的组合可诱导剂量依赖性的亚硝酸盐产生，在孵育4天后观察到峰值水平。当用IL-1α（100单位/毫升）/IFN-γ（10单位/毫升）处理肿瘤来源的、正常卵黄囊、小鼠脑或小鼠主动脉内皮细胞时，与正常内皮细胞相比，肿瘤来源的内皮细胞产生的亚硝酸盐明显更多。IL-1α/IFN-γ产生的亚硝酸盐对一氧化氮合酶抑制剂NG-甲基-L-精氨酸或NG-硝基-L-精氨酸呈剂量依赖性敏感。此外，地塞米松显著抑制经IL-1α/IFN-γ处理的肿瘤来源内皮细胞产生亚硝酸盐。这些研究表明，IL-1α的抗肿瘤活性可能是通过肿瘤来源的内皮细胞产生NO介导的。
