Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response
Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response
复制标题
DOI：
10.1182/blood.v89.3.910
复制
发表时间：
1997-02-01
期刊：
影响因子：
20.3
通讯作者：
Caligiuri, MA
中科院分区：
文献类型：
--
作者：
Ross, ME;Caligiuri, MA
干扰素-γ (IFN-gamma) 对于有效抵抗感染的先天免疫反应至关重要。源自活化 T 细胞 (IL-2) 和单核细胞 (IL-12) 的白细胞介素 (IL) 组合。或单独的单核细胞（IL-15 和 IL-12），诱导自然杀伤 (NK) 细胞最佳产生 IFN-γ。人类 NK 细胞下调 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诱导 NK 细胞凋亡。 Fas、bcl-2 或 bar 似乎不参与此过程。细胞因子诱导的人类 NK 细胞凋亡的机制似乎涉及 NK 细胞产生肿瘤坏死因子-α (TNF-α)。中和 TNF-α 或抑制 TNF-α 与 p80 TNF-α 受体的结合可部分抑制细胞凋亡。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。 CD3(-)CD56(+) NK 白血病细胞系与 IL-2 和 IL-12 或 IL-15 和 IL-12 共刺激可在体外诱导细胞凋亡，与化疗药物联合使用时细胞凋亡增加。总之，通过 IL-2 受体和 IL-12 受体共刺激人类 NK 细胞会诱导显着的 IFN-γ 产生，随后发生 NK 细胞凋亡和 IFN-γ 产生下降。因此，激活这种先天免疫反应的细胞因子也可能通过细胞凋亡来限制它。这一新的观察结果可能对感染过程中先天免疫反应的调节、联合细胞因子疗法的毒性以及 NK 细胞白血病的治疗产生影响。 (C) 1997 年，美国血液学会。
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 bar 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. (C) 1997 by The American Society of Hematology.