Trotta Rossana, Ciarlariello David, Dal Col Jessica, Allard Jeffrey, Neviani Paolo, Santhanam Ramasamy, Mao Hsiaoyin, Becknell Brian, Yu Jianhua, Ferketich Amy K, Thomas Brittany, Modi Aalok, Blaser Bradley W, Perrotti Danilo, Caligiuri Michael A
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
J Exp Med. 2007 Oct 1;204(10):2397-405. doi: 10.1084/jem.20070419. Epub 2007 Sep 17.
Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon-gamma (IFN-gamma), which is a critical factor for immune surveillance of cancer and monocyte clearance of infection. We show that SET, which is a potent inhibitor of protein phosphatase type 2A (PP2A) activity, is highly expressed in human CD56bright NK cells, which produce more IFN-gamma than CD56dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN-gamma gene expression in monokine-stimulated NK cells. In contrast, RNAi-mediated suppression of SET expression renders NK cells inefficient in producing high levels of IFN-gamma in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN-gamma gene expression in NK cells. In fact, treatment of primary human NK cells with the PP2A activator 1,9-dideoxy-forskolin, as well as administration of the drug to C57BL/6 mice, significantly reduced NK-dependent IFN-gamma production in response to monokine treatment. Further, SET knockdown or pharmacologic activation of PP2A diminished extracellular signal-regulated kinase 1/2, p65RelA, signal transducer and activator of transduction 4 (STAT4), and STAT5 activity in monokine-stimulated NK cells, potentially contributing to the reduction in IFN-gamma gene expression. Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-gamma.
单核因子（即白细胞介素[IL]-12、-18和-15）诱导自然杀伤（NK）细胞产生γ干扰素（IFN-γ），这是癌症免疫监视和感染单核细胞清除的关键因子。我们发现，作为蛋白磷酸酶2A（PP2A）活性的强效抑制剂的SET，在人CD56bright NK细胞中高表达，该细胞比CD56dim NK细胞产生更多的IFN-γ。原发性人NK细胞经单核因子刺激后SET上调。此外，SET的异位过表达显著增强了单核因子刺激的NK细胞中IFN-γ基因的表达。相反，RNAi介导的SET表达抑制使NK细胞在响应单核因子共刺激时无法高效产生高水平的IFN-γ。从机制上讲，SET对PP2A活性的抑制对NK细胞中IFN-γ基因的表达很重要。事实上，用PP2A激活剂1,9-二脱氧佛司可林处理原发性人NK细胞，以及给C57BL/6小鼠施用该药物，均显著降低了NK细胞对单核因子处理的依赖性IFN-γ产生。此外，SET敲低或PP2A的药理学激活降低了单核因子刺激的NK细胞中细胞外信号调节激酶1/2、p65RelA、信号转导和转录激活因子4（STAT4）以及STAT5的活性，这可能导致IFN-γ基因表达的降低。因此，SET的表达对于抑制PP2A磷酸酶活性至关重要，否则PP2A磷酸酶活性会通过损害NK细胞产生IFN-γ来限制NK细胞的抗肿瘤和/或抗炎功能。
