title: IκBζ augments IL-12- and IL-18-mediated IFN-γ production in human NK cells.
abstract: Interferon-γ (IFN-γ) production by natural killer (NK) cells and cytotoxic lymphocytes is a key component of innate and adaptive immune responses. Because inhibitor of κB-ζ (IκBζ), a Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) inducible transcription factor, regulates IFN-γ production in KG-1 cells, we tested IκBζ's role in the classic lymphocyte pathway of IL-12/IL-18-induced IFN-γ. Upon stimulation with IL-12/IL-18, monocyte-depleted human peripheral blood lymphocytes expressed the 79-kDa form of IκBζ and released IFN-γ. CD56(+) NK cells were shown to be the IκBζ-producing lymphocyte subpopulation, which also released abundant IFN-γ in response to IL-12/IL-18. Importantly, IκBζ was undetectable in CD56(-) lymphocytes where IFN-γ release was 10-fold lower. In addition, small interfering RNA knockdown of IκBζ suppressed IFN-γ expression in CD56(+) cells. The association of IκBζ with the IFN-γ promoter was documented by chromatin immunoprecipitation. IFN-γ promoter activity from IκBζ overexpression was confirmed by luciferase reporter assay. Finally, IκBζ coprecipitated with p65 and p50 NF-κB in NK cells in response to IL-12/IL-18, suggesting that IκBζ's effects on IFN-γ promoter activity are coregulated by NF-κB. These results suggest that IκBζ functions as an important regulator of IFN-γ in human NK cells, further expanding the class of IκBζ-modulated genes.
authors.affiliation: Pulmonary, Allergy, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Raices
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Seshadri
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins; D015151:Immunoblotting; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D020382:Interleukin-18; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D018664:Interleukin-12; D007371:Interferon-gamma