Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J Leukoc Biol. 2020 Apr;107(4):663-671. doi: 10.1002/JLB.3A0120-379RR. Epub 2020 Feb 4.
This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL-33 contributes to enhanced cytokine expression by IL-12 stimulated human NK cells. While IL-33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL-12 to provoke IFN-γ. We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL-33, potentially consistent with levels in tissue microenvironments, synergize with IL-12 to induce secretion of additional cytokines, including TNF and GM-CSF. IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-γ and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL-12 in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.
本研究检验了一个假设，即生理相关浓度的 IL-33 激活 MAPK 有助于增强 IL-12 刺激的人自然杀伤 (NK) 细胞中的细胞因子表达。虽然 IL-33 经典地触发 2 型细胞因子反应，但这种细胞因子也可以与 1 型细胞因子（如 IL-12）协同作用，引发 IFN-γ。我们表明，皮克浓度的 IL-12 和 IL-33 足以促进人 NK 细胞产生强大的 IFN-γ 分泌，远远超过单独对任何一种细胞因子的反应。纳克浓度的 IL-33，可能与组织微环境中的水平一致，与 IL-12 协同诱导额外细胞因子的分泌，包括 TNF 和 GM-CSF。IL-33 诱导的人 NK 细胞 p38 MAPK 途径的激活对于对 IL-12 的 IFN-γ 和 TNF 的增强释放是至关重要的。在机制上，IL-33 诱导的 p38 MAPK 信号增强了 IFNG 转录物的稳定性，并触发 A 型整合素金属蛋白酶结构域 17 (ADAM17) 介导的 TNF 从细胞表面的切割。这些数据支持我们的假设，并表明在 IL-33 存在下 NK 细胞对 IL-12 的敏感性改变可能对与混合细胞因子环境相关的疾病（如哮喘和慢性阻塞性肺疾病）具有重要影响。
