IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18

Tohru Miyake, Takashi Satoh, Hiroki Kato, Kazufumi Matsushita, Yutaro Kumagai, Alexis Vandenbon, Tohru Tani, Tatsushi Muta, Shizuo Akira, Osamu Takeuchi

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)17680-17685
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
Publication statusPublished - 2010 Oct 12
Externally publishedYes


  • IFN-γ
  • STAT4
  • Transcription
  • Virus infection

ASJC Scopus subject areas

  • General


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