Rabinowich H, Herberman R B, Whiteside T L
Department of Pathology, University of Pittsburgh, School of Medicine, Pennsylvania 15213.
Cell Immunol. 1993 Dec;152(2):481-98. doi: 10.1006/cimm.1993.1306.
Accessory functions of cellular adhesion molecules (CAM) in activation, adhesion, migration, and cytotoxicity of natural killer (NK) cells are partly dependent on activation by cytokines. We studied effects of interleukin 12 (IL12) on expression and function of adhesion molecules on human NK cells and compared them to the effects mediated by IL2. Target binding of NK cells was significantly increased by IL12, leading to an increased level of conjugate formation with K562 target cells as well as enhanced binding to tumor monolayers. IL12 also induced significant levels of cytotoxicity against fresh tumor cell targets in purified human NK cells. IL12 significantly enhanced adhesion and subsequent migration of NK cells through 3-microns-pore-size polycarbonate filters. However, IL2 was a more potent activator of these functions, which have been shown to be partly mediated by CD2, CD58, beta 2 integrins, and ICAM-1. As assessed by flow cytometry, IL12 also induced significant up-regulation in the proportion or mean fluorescence intensity of NK cells positive for the following activation markers and adhesion molecules: CD25, HLA-DR, CD69, CD71, CD56, CD2, and CD54. Among the beta 2 integrins, IL12 selectively increased expression of CD11a on NK cells, although to a significantly lower level than that induced by IL2. IL12 had different in vitro effects than IL2 on expression and function of the beta 1 integrins. Whereas IL2 induced marked up-regulation in expression of the beta 1 integrins, CD49b, -c, -d, and -e, IL12 had no demonstrable effect over a wide range of concentrations. In addition, while IL2-activated NK cells showed significantly increased integrin-dependent adhesion to fibronectin- or laminin-coated plates, IL12-activated cells were less adherent to fibronectin and were unchanged in their adherence to laminin. Our data demonstrate that IL12 is involved in interactions of NK cells with fresh or cultured tumor cell targets, biologic substrates, or extracellular matrix molecules. Although the magnitude of its in vitro effects on adhesion-dependent functions of NK cells was significantly smaller than that of IL2, lower doses of IL12 were required to up-regulate functions of CAM, and this may be an attractive feature of IL12 as a potential therapeutic cytokine.
细胞黏附分子（CAM）在自然杀伤（NK）细胞的激活、黏附、迁移及细胞毒性方面的辅助功能部分依赖于细胞因子的激活作用。我们研究了白细胞介素12（IL12）对人NK细胞黏附分子表达及功能的影响，并将其与IL2介导的效应进行比较。IL12显著增加了NK细胞的靶细胞结合能力，导致与K562靶细胞形成共轭物的水平升高，以及与肿瘤单层细胞的结合增强。IL12还在纯化的人NK细胞中诱导了对新鲜肿瘤细胞靶标的显著细胞毒性水平。IL12显著增强了NK细胞通过3微米孔径聚碳酸酯滤膜的黏附及随后的迁移能力。然而，IL2是这些功能更有效的激活剂，这些功能已被证明部分由CD2、CD58、β2整合素和ICAM-1介导。通过流式细胞术评估，IL12还诱导了以下激活标记物和黏附分子阳性的NK细胞比例或平均荧光强度的显著上调：CD25、HLA-DR、CD69、CD71、CD56、CD2和CD54。在β2整合素中，IL12选择性地增加了NK细胞上CD11a的表达，尽管其水平明显低于IL2诱导的水平。IL12对β1整合素的表达和功能的体外作用与IL2不同。虽然IL2诱导了β1整合素CD49b、-c、-d和-e表达的显著上调，但IL12在广泛的浓度范围内没有明显作用。此外，虽然IL2激活的NK细胞显示出整合素依赖性黏附到纤连蛋白或层粘连蛋白包被板上的能力显著增加，但IL12激活的细胞对纤连蛋白的黏附性较低，对层粘连蛋白的黏附性没有变化。我们的数据表明，IL12参与了NK细胞与新鲜或培养的肿瘤细胞靶标、生物底物或细胞外基质分子的相互作用。虽然其对NK细胞黏附依赖性功能的体外作用程度明显小于IL2，但上调CAM功能所需的IL12剂量较低，这可能是IL12作为潜在治疗性细胞因子的一个有吸引力的特征。
