Department of Anesthesiology and Surgical Intensive Care Medicine, Institute for Innate Immunoscience (MI3), University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Cells. 2020 Mar 17;9(3):734. doi: 10.3390/cells9030734.
Natural killer (NK) cells are among the first innate immune cells to arrive at sites of tissue inflammation and regulate the immune response to infection and tumors by the release of cytokines including interferon (IFN)γ. In vitro exposure to the innate cytokines interleukin 15 (IL-15) and IL-12/IL-18 enhances NK cell IFNγ production which, beyond 16 h of culture, was shown to depend on metabolic switching to glycolysis. NK effector responses are, however, rapid by comparison. Therefore, we sought to evaluate the importance of glycolysis for shorter-term IFNγ production, considering glucose deprivation and hypoxia as adverse tissue inflammation associated conditions. Treatments with IL-15 for 6 and 16 h were equally effective in priming early IFNγ production in human NK cells in response to secondary IL-12/IL-18 stimulation. Short-term priming was not associated with glycolytic switching but induced the release of IFNγ and, additionally, CCL3, CCL4 and CCL5 from both normoxic and hypoxic NK cells in an equally efficient and, unexpectedly, glucose independent manner. We conclude that release of IFNγ and CC chemokines in the early innate immune response is a metabolically autonomous NK effector program.
自然杀伤 (NK) 细胞是最早到达组织炎症部位的先天免疫细胞之一，通过释放细胞因子（包括干扰素 (IFN)γ）来调节对感染和肿瘤的免疫反应。体外暴露于先天细胞因子白细胞介素 15 (IL-15) 和 IL-12/IL-18 会增强 NK 细胞 IFNγ 的产生，超过 16 小时的培养后，发现这依赖于代谢向糖酵解的转换。然而，NK 效应器反应相对较快。因此，我们试图评估糖酵解对短期 IFNγ 产生的重要性，同时考虑葡萄糖剥夺和缺氧作为与组织炎症相关的不利条件。IL-15 处理 6 和 16 小时同样有效地在二次 IL-12/IL-18 刺激下引发人类 NK 细胞早期 IFNγ 的产生。短期启动与糖酵解转换无关，但以同样有效的方式诱导 IFNγ 的释放，并且，出乎意料的是，以葡萄糖独立的方式从正常氧和缺氧 NK 细胞中释放 CCL3、CCL4 和 CCL5。我们得出结论，早期先天免疫反应中 IFNγ 和 CC 趋化因子的释放是一种代谢自主的 NK 效应器程序。
