Laboratory of Host Defense, Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17680-5. doi: 10.1073/pnas.1012977107. Epub 2010 Sep 27.
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.
IκBζ，由 Nfibiz 编码，是一种具有锚蛋白重复序列的核 IκB 样蛋白。已经表明，IκBζ 可调节巨噬细胞中的 IL-6 产生和 T 细胞中的 Th17 发育。然而，IκBζ 在自然杀伤 (NK) 细胞中的作用尚未得到理解。在本研究中，我们发现 IκBζ 在 NK 细胞中对 IL-18 的反应中迅速诱导表达，但在 T 细胞中则不然。对 Nfkbiz(-/-) 小鼠的分析表明，IκBζ 对于 NK 细胞在受到 IL-12 和/或 IL-18 刺激时产生 IFN-γ 和细胞毒性活性是必不可少的。在 Nfkbiz(-/-) NK 细胞中，IL-12/IL-18 介导的基因诱导受到严重损害。虽然 STAT4 的磷酸化在受到 IL-12 刺激时被正常诱导，但 STAT4 未被募集到 Nfkbiz(-/-) NK 细胞中的 Ifng 基因区域。在 Nfkbiz(-/-) NK 细胞中，Ifng 区域上的组蛋白 H3 K9 乙酰化也被阻断。IκBζ 被募集到 Ifng 基因的近端启动子区域，并且 IκBζ 与 IL-12 的共表达激活了 Ifng 启动子。此外，Nfkbiz(-/-) 小鼠对小鼠 MCMV 感染高度敏感。综上所述，这些结果表明 IκBζ 对于 NK 细胞的激活和抗病毒宿主防御反应是必不可少的。
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