IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18
IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18
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DOI：
10.1073/pnas.1012977107
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发表时间：
2010-10-12
影响因子：
11.1
通讯作者：
Takeuchi, Osamu
中科院分区：
文献类型：
--
作者：
Miyake, Tohru;Satoh, Takashi;Takeuchi, Osamu
I kappa B zeta由Nfibiz编码，是一种含有锚蛋白重复序列的核I kappa B样蛋白。已显示I κ B ζ调节巨噬细胞中的IL-6产生和T细胞中的Th 17发育。然而，I κ B zeta在自然杀伤（NK）细胞中的作用尚未被理解。在本研究中，我们发现，I κ B zeta的表达迅速诱导响应IL-18在NK细胞，但不是在T细胞。对Nfkbiz（-/-）小鼠的分析显示I κ B ζ对于响应IL-12和/或IL-18刺激的NK细胞中IFN-γ产生和细胞毒性活性的产生是必需的。IL-12/IL-18介导的基因诱导在Nfkbiz（-/-）NK细胞中严重受损。尽管STAT 4的磷酸化通常由IL-12刺激诱导，但在Nfkbiz（-/-）NK细胞中，STAT 4不被募集到Ifng基因区域。在Nfkbiz（-/-）NK细胞中，Ifng区域上的组蛋白3 K9的乙酰化也被废除。I κ B zeta在Ifng基因的近端启动子区募集，并且I κ B zeta与IL-12一起过表达激活Ifng启动子。此外，Nfkbiz（-/-）小鼠对小鼠MCMV感染高度易感。综上所述，这些结果表明I κ B ζ对于NK细胞的活化和抗病毒宿主防御反应是必需的。
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.