IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18.
IκBζ, encoded by Nfibiz, is a nuclear IκB-like protein harboring ankyrin repeats. IκBζ has been shown to regulate IL-6 production in macrophages and Th17 development in T cells. However, the role of IκBζ in natural killer (NK) cells has not be understood. In the present study, we found that the expression of IκBζ was rapidly induced in response to IL-18 in NK cells, but not in T cells. Analysis of Nfkbiz(-/-) mice revealed that IκBζ was essential for the production of IFN-γ production and cytotoxic activity in NK cells in response to IL-12 and/or IL-18 stimulation. IL-12/IL-18-mediated gene induction was profoundly impaired in Nfkbiz(-/-) NK cells. Whereas the phosphorylation of STAT4 was normally induced by IL-12 stimulation, STAT4 was not recruited to the Ifng gene regions in Nfkbiz(-/-) NK cells. Acetylation of histone 3 K9 on Ifng regions was also abrogated in Nfkbiz(-/-) NK cells. IκBζ was recruited on the proximal promoter region of the Ifng gene, and overexpression of IκBζ together with IL-12 activated the Ifng promoter. Furthermore, Nfkbiz(-/-) mice were highly susceptible to mouse MCMV infection. Taken together, these results demonstrate that IκBζ is essential for the activation of NK cells and antiviral host defense responses.
Miyake
Tohru
T
Laboratory of Host Defense, Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Satoh
Takashi
T
Kato
Hiroki
H
Matsushita
Kazufumi
K
Kumagai
Yutaro
Y
Vandenbon
Alexis
A
Tani
Tohru
T
Muta
Tatsushi
T
Akira
Shizuo
S
Takeuchi
Osamu
O
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D047369:Chromatin Immunoprecipitation; D003601:Cytotoxicity Tests, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology*; D006566:Herpesviridae Infections / Q000235:genetics; D006657:Histones / Q000378:metabolism; D020672:I-kappa B Proteins / Q000276:immunology* / Q000378:metabolism; D015151:Immunoblotting; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D018146:Muromegalovirus; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D006657:Histones; D020672:I-kappa B Proteins; D020382:Interleukin-18; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma