Ellis T M, McKenzie R S, Simms P E, Helfrich B A, Fisher R I
Section of Hematology/Oncology, Loyola University Stritch School of Medicine, Maywood, IL 60153.
J Immunol. 1989 Dec 15;143(12):4282-6.
By traditional definitions, NK cells can be activated by cytokines to exhibit two functionally distinct levels of cytotoxicity. Whereas IL-2-mediated activation of NK cells leads to the development of lymphokine-activated killer (LAK) cytotoxicity, characterized by the acquisition of cytolytic activity against NK-resistant targets, IFN-treated NK cells become activated without the acquisition of novel cytolytic specificities. In this study we show that NK cells activated by 18 to 24 h of stimulation with either IFN-alpha or IFN-gamma do acquire LAK cytolytic activity, demonstrated by the ability of IFN-treated PBMC to lyse NK-resistant COLO 205 cells as well as fresh tumor targets. The level of IFN-alpha-induced LAK activity was significantly greater than that induced by IFN-gamma, although IL-2-induced LAK activity was considerably greater than IFN-alpha-induced LAK cytotoxicity. Maximal IFN-induced LAK cytotoxicity occurred after 24 h of culture, and occurred with the use of IFN-alpha at 500 U/ml and IFN-gamma at 1000 U/ml. Whereas neutralizing antibody experiments demonstrated that IFN-alpha-induced LAK activation did not involve the participation of endogenously produced IL-2, the partial inhibition (63%) of IFN-gamma-induced LAK cytotoxicity by anti-IL-2 and of IL-2-induced LAK by anti-IFN-gamma (33.3%) indicates that the induction of LAK cytotoxicity by either of these individual cytokines involves the endogenous production and participation of the other cytokine. Similar to IL-2-induced LAK cells, phenotypic analysis revealed that IFN-alpha/gamma LAK cells were Leu-19+, although the Leu 19"dim"+ subset exhibited greater IFN-induced LAK activity than the Leu-19"bright"+ subset. The results of this study clearly demonstrate that IFN-alpha and IFN-gamma induce classic LAK activity and IFN-gamma plays a participatory role in the optimal induction of LAK cells by IL-2.
根据传统定义，自然杀伤细胞（NK细胞）可被细胞因子激活，表现出两种功能上不同的细胞毒性水平。白细胞介素-2（IL-2）介导的NK细胞激活会导致淋巴因子激活的杀伤细胞（LAK）细胞毒性的产生，其特征是获得针对NK抗性靶标的溶细胞活性，而经干扰素（IFN）处理的NK细胞在未获得新的溶细胞特异性的情况下被激活。在本研究中，我们表明，用IFN-α或IFN-γ刺激18至24小时激活的NK细胞确实获得了LAK溶细胞活性，这通过经IFN处理的外周血单核细胞（PBMC）裂解NK抗性的COLO 205细胞以及新鲜肿瘤靶标的能力得以证明。IFN-α诱导的LAK活性水平显著高于IFN-γ诱导的水平，尽管IL-2诱导的LAK活性远高于IFN-α诱导的LAK细胞毒性。最大的IFN诱导的LAK细胞毒性在培养24小时后出现，使用500 U/ml的IFN-α和1000 U/ml的IFN-γ时出现。虽然中和抗体实验表明IFN-α诱导的LAK激活不涉及内源性产生的IL-2的参与，但抗IL-2对IFN-γ诱导的LAK细胞毒性的部分抑制（63%）以及抗IFN-γ对IL-2诱导的LAK的部分抑制（33.3%）表明，这两种单独的细胞因子诱导LAK细胞毒性都涉及另一种细胞因子的内源性产生和参与。与IL-2诱导的LAK细胞类似，表型分析显示IFN-α/γ LAK细胞为Leu-19+，尽管Leu 19“dim”+亚群表现出比Leu-19“bright”+亚群更高的IFN诱导的LAK活性。本研究结果清楚地表明IFN-α和IFN-γ诱导经典的LAK活性，并且IFN-γ在IL-2对LAK细胞的最佳诱导中起参与作用。
