The PP2A inhibitor SET regulates natural killer cell IFN-gamma production.
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.
Trotta
Rossana
R
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA. rossana.trotta@osumc.edu
Ciarlariello
David
D
Dal Col
Jessica
J
Allard
Jeffrey
J
Neviani
Paolo
P
Santhanam
Ramasamy
R
Mao
Hsiaoyin
H
Becknell
Brian
B
Yu
Jianhua
J
Ferketich
Amy K
AK
Thomas
Brittany
B
Modi
Aalok
A
Blaser
Bradley W
BW
Perrotti
Danilo
D
Caligiuri
Michael A
MA
D000818:Animals; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D056488:Histone Chaperones; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015846:Monokines / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D015846:Monokines; C513473:SET protein, human; D014157:Transcription Factors; D007371:Interferon-gamma; D010749:Phosphoprotein Phosphatases