Ross M E, Caligiuri M A
Department of Hematologic Oncology and Bone Marrow Transplantation, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Blood. 1997 Feb 1;89(3):910-8.
Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.
干扰素-γ（IFN-γ）对于针对感染的有效先天性免疫反应至关重要。源自活化T细胞的白细胞介素（ILs）（IL-2）和单核细胞（IL-12）的组合，或单独的单核细胞（IL-15和IL-12），可诱导自然杀伤（NK）细胞最佳地产生IFN-γ。人类NK细胞下调其IFN-γ产生的机制尚不清楚。在这里，我们表明，诱导人类NK细胞产生IFN-γ的相同细胞因子随后会诱导NK细胞凋亡。Fas、bcl-2或bax似乎不参与此过程。细胞因子诱导的人类NK细胞凋亡机制似乎涉及NK细胞产生肿瘤坏死因子-α（TNF-α）。TNF-α的中和或TNF-α与p80 TNF-α受体结合的抑制可部分抑制凋亡。转化生长因子-β可抑制细胞因子诱导的NK细胞产生IFN-γ和TNF-α，也可减少细胞因子诱导的NK细胞凋亡。用IL-2和IL-12或IL-15和IL-12对CD3-CD56+NK白血病细胞系进行共刺激可在体外诱导凋亡，与化疗药物联合使用时凋亡增加。总之，通过IL-2受体和IL-12受体对人类NK细胞进行共刺激可诱导显著的IFN-γ产生，随后是NK细胞凋亡和IFN-γ产生下降。因此，激活这种先天性免疫反应的细胞因子也可能通过凋亡来限制它。这一新颖的观察结果可能对感染期间先天性免疫反应的调节、联合细胞因子治疗的毒性以及NK细胞白血病的治疗具有重要意义。
