title: miR-155 regulates IFN-γ production in natural killer cells.
abstract: MicroRNAs (miRs) are small, noncoding RNA molecules with important regulatory functions whose role in regulating natural killer (NK) cell biology is not well defined. Here, we show that miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. Over-expression of miR-155 enhanced induction of IFN-γ by IL-12 and IL-18 or CD16 stimulation, whereas knockdown of miR-155 or its disruption suppressed IFN-γ induction in monokine and/or CD16-stimulated NK cells. These effects on the regulation of NK cell IFN-γ expression were found to be mediated at least in part via miR-155's direct effects on the inositol phosphatase SHIP1. Consistent with this, we observed that modulation of miR-155 overrides IL-12 and IL-18-mediated regulation of SHIP1 expression in NK cells. Collectively, our data indicate that miR-155 expression is regulated by stimuli that strongly induce IFN-γ in NK cells such as IL-12, IL-18, and CD16 activation, and that miR-155 functions as a positive regulator of IFN-γ production in human NK cells, at least in part via down-regulating SHIP1. These findings may have clinical relevance for targeting miR-155 in neoplastic disease.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA. rossana.trotta@osumc.edu
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Ciarlariello
authors.forename: Srirama
authors.initials: S
authors.lastname: Josyula
authors.forename: Charlene
authors.initials: C
authors.lastname: Mao
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D017452:Receptors, IgG; D018664:Interleukin-12; 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