title: Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation.
abstract: Monocyte cytokines (ie, monokines) induce natural killer (NK) cells to produce interferon-gamma (IFN-gamma), which is critical for monocyte clearance of infectious pathogens and tumor surveillance. Human CD56bright NK cells produce far more IFN-gamma in response to monokines than do CD56dim NK cells. The kinases and phosphatases involved in regulating IFN-gamma production by monokine-activated NK cells are not clearly identified. SHIP1 is a 5' inositol phosphatase that dephosphorylates the phosphatidylinositol-3 kinase (PI-3K) product PI3,4,5P3. Here, we show that constitutive expression of SHIP1 is distinctly lower in CD56bright NK cells compared with CD56dim NK cells, suggesting it could be an important negative regulator of IFN-gamma production in monokine-activated NK cells. Indeed, overexpression of SHIP1 in CD56bright NK cells followed by monokine activation substantially lowered IFN-gamma production. This effect was not seen when NK cells were infected with a SHIP1 mutant containing an inactive catalytic domain. Finally, NK cells in SHIP1-/- mice produced more IFN-gamma in response to monokines in vivo than did NK cells from wild-type mice. Collectively, these results demonstrate that SHIP1 negatively regulates monokine-induced NK cell IFN-gamma production in vitro and in vivo and provide the first molecular explanation for an important functional distinction observed between CD56bright and CD56dim human NK subsets.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Colelge of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Robin
authors.initials: R
authors.lastname: Parihar
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Allard
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D019002:CD56 Antigen / Q000235:genetics*; D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015846:Monokines / Q000494:pharmacology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D013268:Stimulation, Chemical
chemical_list: D019002:CD56 Antigen; D007295:Inositol Phosphates; D015846:Monokines; C118500:inositol 3,4,5-trisphosphate; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases