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

摘要

IκBζ, encoded by Nfibiz, is a nuclear lkB-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 IkBζ in natural killer (NK) cells has not be understood. In the present study, we found that the expression of IkBζ was rapidly induced in response to IL-18 in NK cells, but not in T cells. Analysis of Nfkbiz~(-/-) mice revealed that IkBζ was essential for the production rnof IFN-γ production and cytotoxic activity in NK cells in response rnto 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 lfng regions was also abrogated in Nfkbiz~(-/-) NK cells. IkBζ 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.