Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon-γ (IFN-γ), 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-γ than CD56dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN-γ 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-γ in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN-γ 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-γ 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-γ 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-γ.
The PP2A inhibitor SET regulates natural killer cell IFN-γ production
Abbreviations used: APC, allophycocyanin; CTS, cytostatin; ERK, extracellular signal-regulated kinase; I1PP2A, PP2A inhibitor 1; I2PP2A, PP2A inhibitor 2; MAP, mitogen-activated protein; MAPK, MAP kinase; PP2A, protein phosphatase type 2A; shRNA, short hairpin RNA; PP2Ac, PP2A catalytic subunit; STAT, signal transducer and activator of transduction.
M.A. Caligiuri and D. Perrotti contributed equally to this paper.
Rossana Trotta, David Ciarlariello, Jessica Dal Col, Jeffrey Allard, Paolo Neviani, Ramasamy Santhanam, Hsiaoyin Mao, Brian Becknell, Jianhua Yu, Amy K. Ferketich, Brittany Thomas, Aalok Modi, Bradley W. Blaser, Danilo Perrotti, Michael A. Caligiuri; The PP2A inhibitor SET regulates natural killer cell IFN-γ production . J Exp Med 1 October 2007; 204 (10): 2397–2405. doi: https://doi.org/10.1084/jem.20070419
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