Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20892, USA.
Mol Immunol. 2010 Oct;47(16):2604-10. doi: 10.1016/j.molimm.2010.05.290. Epub 2010 Oct 30.
Human natural killer (NK) cells constitute an important cellular component of innate immunity, capable of killing infected and transformed cells. The proliferation and activation of NK cells are regulated by various cytokines. Interleukin-18 (IL-18) promotes NK cell activation; however, whether the effects of IL-18 on NK cell are associated with other cytokines is still unknown. In this study, we observed that IL-18 induced NK cell apoptosis and inhibited NK cell expansion in the presence of low concentrations of interleukin-2 (IL-2), while high concentrations of IL-2 overcame these effects of IL-18, and high concentrations of IL-2 promoted the stimulatory activity of IL-18 on NK cells. At a low concentration of IL-2, IL-18 induced NK cell apoptosis in part through activation of the FasL/Fas- and TNFα/TNFR-mediated death receptor signaling by enhancing FasL expression and inhibiting c-FLIP(long) expression. However, high concentrations of IL-2 strongly blocked IL-18-induced NK cell apoptosis through alleviating IL-18-induced FasL expression and activation of Fas-mediated death signaling and increasing anti-apoptosis molecule (Bcl-X(L)). These results reveal that the effects of IL-18 on human NK cell are associated with IL-2 concentration and suggest the importance of IL-2 level in cytokine immunotherapy.
人类自然杀伤 (NK) 细胞构成固有免疫的重要细胞成分，能够杀伤感染和转化的细胞。NK 细胞的增殖和激活受各种细胞因子的调节。白细胞介素-18 (IL-18) 促进 NK 细胞的激活；然而，IL-18 对 NK 细胞的影响是否与其他细胞因子有关尚不清楚。在这项研究中，我们观察到在低浓度白细胞介素-2 (IL-2) 的存在下，IL-18 诱导 NK 细胞凋亡并抑制 NK 细胞扩增，而高浓度的 IL-2 克服了 IL-18 的这些作用，并且高浓度的 IL-2 促进了 IL-18 对 NK 细胞的刺激活性。在低浓度的 IL-2 下，IL-18 通过增强 FasL 表达和抑制 c-FLIP(long) 表达，部分通过激活 FasL/Fas 和 TNFα/TNFR 介导的死亡受体信号通路诱导 NK 细胞凋亡。然而，高浓度的 IL-2 通过减轻 IL-18 诱导的 FasL 表达和激活 Fas 介导的死亡信号以及增加抗凋亡分子 (Bcl-X(L))，强烈阻断 IL-18 诱导的 NK 细胞凋亡。这些结果表明，IL-18 对人 NK 细胞的影响与 IL-2 浓度有关，并表明 IL-2 水平在细胞因子免疫治疗中的重要性。
