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

I kappa B zeta, encoded by Nfibiz, is a nuclear I kappa B-like protein harboring ankyrin repeats. I kappa B zeta has been shown to regulate IL-6 production in macrophages and Th17 development in T cells. However, the role of I kappa B zeta in natural killer (NK) cells has not be understood. In the present study, we found that the expression of I kappa B zeta was rapidly induced in response to IL-18 in NK cells, but not in T cells. Analysis of Nfkbiz(-/-) mice revealed that I kappa B zeta was essential for the production of IFN-gamma 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. I kappa B zeta was recruited on the proximal promoter region of the Ifng gene, and overexpression of I kappa B zeta together with IL-12 activated the Ifng promoter. Furthermore, Nfkbiz(-/-) mice were highly susceptible to mouse MCMV infection. Taken together, these results demonstrate that I kappa B zeta is essential for the activation of NK cells and antiviral host defense responses.