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The PP2A inhibitor SET regulates natural killer cell IFN-gamma production.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2007 Oct 01; Vol. 204 (10), pp. 2397-405. Date of Electronic Publication: 2007 Sep 17. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Animals
Cells, Cultured
Chromosomal Proteins, Non-Histone genetics
DNA-Binding Proteins
Enzyme Activation
Gene Expression Regulation
Histone Chaperones
Humans
Killer Cells, Natural drug effects
Killer Cells, Natural immunology
Mice
Mice, Inbred C57BL
Monokines pharmacology
Signal Transduction
Transcription Factors genetics
Chromosomal Proteins, Non-Histone metabolism
Interferon-gamma biosynthesis
Killer Cells, Natural metabolism
Phosphoprotein Phosphatases antagonists & inhibitors
Phosphoprotein Phosphatases metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1007
- Volume :
- 204
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 17875674
- Full Text :
- https://doi.org/10.1084/jem.20070419