Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-gamma in vivo.
Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-gamma in vivo.
复制标题
Interleukin-18 与 IL-2 结合可增强自然杀伤细胞活性，而不会在体内诱导大量 IFN-γ。
DOI：
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发表时间：
2000
影响因子：
2.3
通讯作者：
M. Kurimoto
中科院分区：
文献类型：
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作者：
N. Arai;S. Akamatsu;S. Arai;Y. Toshimori;T. Hanaya;T. Tanimoto;M. Ikeda;M. Tomura;H. Fujiwara;M. Kurimoto
已知白介素18(IL-18)与IL-12或IL-2联合在体外可协同增强小鼠自然杀伤(NK)细胞活性。然而，也有研究表明，同时给小鼠注射IL-18和IL-12会诱导血清中异常大量的干扰素-γ。在这项研究中，我们检测了IL-18和IL-2的组合在诱导毒性的同时对体内NK细胞激活的影响。与IL-18和IL-12联合应用相比，IL-18和IL-2联合应用BALB/c小鼠3天既没有引起高水平的干扰素-γ产生，也没有引起其他明显的副作用。与IL-18或IL-2单独用药相比，联合用药组小鼠脾DX-5(PAN-NK细胞标记物)阳性细胞数显著增加，标准细胞毒试验显示脾NK细胞活性显著增强。同时观察到IL-18和IL-2处理的小鼠对同基因结肠癌细胞的脾细胞毒作用增强。与此体外观察一致，联合治疗对静脉注射后肺转移的抑制作用明显增强。注射结肠26肿瘤细胞比单独注射任何一种细胞因子的治疗效果要好。这些结果表明，IL-18联合IL-2可增强体内NK细胞的活性，并有助于抑制肿瘤转移，而不会产生明显的毒性。
Interleukin-18 (IL-18) is known to synergistically enhance murine natural killer (NK) cell activity in vitro when combined with either IL-12 or IL-2. However, it has also been demonstrated that simultaneous administration of IL-18 and IL-12 to mice induces extraordinarily large amounts of interferon-gamma (IFN-gamma) in the serum. In this study, we examined the effects of a combination of IL-18 and IL-2 on in vivo NK cell activation in parallel with the induction of toxicity. In contrast to the IL-18 and IL-12 combination, the combined administration of IL-18 and IL-2 to BALB/c mice for 3 days induced neither high levels of IFN-gamma production nor other visible side effects. When compared with treatment with IL-18 or IL-2 alone, the combined treatment resulted in a significant increase in the number of DX-5 (pan-NK cells marker)-positive cells in spleens and a marked enhancement of splenic NK activity, as determined by standard cytotoxicity assays. Enhanced splenic cytotoxicity generated in the mice treated with both IL-18 and IL-2 was also observed against syngeneic Colon 26 adenocarcinoma cells. Consistent with this in vitro observation, combined treatment produced a significantly stronger inhibitory effect on the pulmonary metastases following i.v. injection of Colon 26 tumor cells than treatment with either cytokine alone. These results suggest that IL-18 combined with IL-2 potentiates in vivo NK cell activity and contributes to inhibition of tumor metastasis without inducing significant toxicity.