Bluman E M, Bartynski K J, Avalos B R, Caligiuri M A
Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
J Clin Invest. 1996 Jun 15;97(12):2722-7. doi: 10.1172/JCI118726.
Once infected by obligate intracellular pathogens, monocytes/macrophages release cytokines that activate natural killer (NK) cells. NK cells in turn produce and secrete monocyte/macrophage activating factors such as interferongamma (IFN-gamma), which are important in the early control of these infections. Here we demonstrate that human NK cells are potent producers of another monocyte/macrophage-activating factor, macrophage inflammatory protein-1 alpha (MIP-1 alpha). Fresh NK cells produce negligible amounts of MIP-1 alpha after stimulation with the monocyte-derived cytokines IL-12, TNF-alpha, IL-1 beta, or IL-10, while stimulation with IL-15 alone results in modest MIP-1 alpha production. Abundant NK cell production MIP-1 alpha is seen after costimulation with IL-12 and IL-15, and is dose-dependent. Combinations of IL-12, with TNF-alpha, IL-1 beta, or IL-10 are substantially less effective inducers of MIP-1 alpha production by NK cells. NK cell MIP-1 alpha mRNA transcripts were detectable within 1 h after costimulation with IL-12 plus IL-15 and steadily increased over 24 h, with a concomitant increase in protein production detectable at 12 h. Resting NK cells constitutively express mRNA transcript for a MIP-1 alpha receptor, and costimulation with IL-12 and IL-15 upregulates its level of expression. Equilibrium binding studies with radioiodinated MIP-1 alpha were consistent with the induction of a single class of high affinity MIP-1 alpha receptors on NK cells costimulated with IL-12 and IL-15. Addition of exogenous MIP-1 alpha to resting NK cells did not enhance cytokine production, but did increase NK cytotoxic activity. The requirement for IL-15 as a critical cofactor for NK cell production MIP-1 alpha suggests a potentially unique role for this monocyte-derived cytokine in combination with IL-12. As MIP-1 alpha is known to potentiate the action of IFN-gamma on monocytes and to suppress human immunodeficiency virus replication, the NK cell's production of MIP-1 alpha may be important during the innate immune response to infection.
一旦被专性细胞内病原体感染，单核细胞/巨噬细胞就会释放激活自然杀伤（NK）细胞的细胞因子。NK细胞继而产生并分泌单核细胞/巨噬细胞激活因子，如γ干扰素（IFN-γ），这些因子在这些感染的早期控制中很重要。在此我们证明，人类NK细胞是另一种单核细胞/巨噬细胞激活因子——巨噬细胞炎性蛋白-1α（MIP-1α）的高效生产者。新鲜NK细胞在用单核细胞衍生的细胞因子白细胞介素-12（IL-12）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）或白细胞介素-10（IL-10）刺激后产生的MIP-1α量可忽略不计，而单独用IL-15刺激仅产生适量的MIP-1α。在用IL-12和IL-15共同刺激后，NK细胞产生大量的MIP-1α，且呈剂量依赖性。IL-12与TNF-α、IL-1β或IL-10的组合对NK细胞产生MIP-1α的诱导作用明显较弱。在用IL-12加IL-15共同刺激后1小时内即可检测到NK细胞的MIP-1α信使核糖核酸转录本，且在24小时内稳步增加，同时在12小时可检测到蛋白质产量随之增加。静息NK细胞组成性表达MIP-1α受体的信使核糖核酸转录本，用IL-12和IL-15共同刺激可上调其表达水平。用放射性碘化MIP-1α进行的平衡结合研究与在用IL-12和IL-15共同刺激的NK细胞上诱导出单一类高亲和力MIP-1α受体的结果一致。向静息NK细胞中添加外源性MIP-1α不会增强细胞因子产生，但会增加NK细胞的细胞毒性活性。IL-15作为NK细胞产生MIP-1α的关键辅助因子，表明这种单核细胞衍生的细胞因子与IL-12结合可能具有潜在独特作用。由于已知MIP-1α可增强IFN-γ对单核细胞的作用并抑制人类免疫缺陷病毒复制，NK细胞产生MIP-1α在对感染的先天免疫反应中可能很重要。
