IκBζ augments IL-12-and IL-18-mediated IFN-γ production in human NK cells
IκBζ augments IL-12-and IL-18-mediated IFN-γ production in human NK cells
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DOI：
10.1182/blood-2010-07-294702
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发表时间：
2011-03-10
期刊：
影响因子：
20.3
通讯作者：
Wewers, Mark D.
中科院分区：
文献类型：
--
作者：
Kannan, Yashaswini;Yu, Jianhua;Wewers, Mark D.
自然杀伤细胞和细胞毒性淋巴细胞产生的干扰素-γ是天然免疫和获得性免疫反应的重要组成部分。由于Kappa B-Zeta(I Kappa B Zeta)是一种Toll样受体(TLR)/白介素1受体(IL-1R)可诱导的转录因子，可调节KG-1细胞产生干扰素-γ，因此我们检测了I kappa B Zeta在IL-12/IL-18诱导的经典淋巴细胞途径中的作用。在IL-12/IL-18刺激下，去单核细胞的人外周血淋巴细胞表达79 kDa形式的I kappa B Zeta，并释放干扰素-γ。CD56(+)NK细胞是产生Ikappa B Zeta的淋巴细胞亚群，也能在IL-12/IL-18刺激下释放大量的干扰素-γ。重要的是，在CD56(-)淋巴细胞中检测不到I kappa B Zeta，因为CD56(-)淋巴细胞的干扰素-γ释放降低了10倍。此外，Ikappa B Zeta的小干扰RNA敲除可抑制CD56(+)细胞中干扰素-γ的表达。染色质免疫沉淀法证明了I kappa B Zeta与干扰素-γ启动子的关联。荧光素酶报告基因分析证实了I kappa B Zeta基因过表达对干扰素-γ启动子活性的影响。IL-12/IL-18刺激后，I-kappa B Zeta与p65和p50核因子-kappa B在NK细胞中共沉淀，提示I-kappa B Zeta对人NK细胞中干扰素-γ启动子活性的影响是由核因子-kappa B共同调节的。(血。2011；117(10)：2855-2863)
Interferon-gamma (IFN-gamma) production by natural killer (NK) cells and cytotoxic lymphocytes is a key component of innate and adaptive immune responses. Because inhibitor of kappa B-zeta (I kappa B zeta), a Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) inducible transcription factor, regulates IFN-gamma production in KG-1 cells, we tested I kappa B zeta's role in the classic lymphocyte pathway of IL-12/IL-18-induced IFN-gamma. Upon stimulation with IL-12/IL-18, monocyte-depleted human peripheral blood lymphocytes expressed the 79-kDa form of I kappa B zeta and released IFN-gamma. CD56(+) NK cells were shown to be the I kappa B zeta-producing lymphocyte subpopulation, which also released abundant IFN-gamma in response to IL-12/IL-18. Importantly, I kappa B zeta was undetectable in CD56(-) lymphocytes where IFN-gamma release was 10-fold lower. In addition, small interfering RNA knockdown of I kappa B zeta suppressed IFN-gamma expression in CD56(+) cells. The association of I kappa B zeta with the IFN-gamma promoter was documented by chromatin immunoprecipitation. IFN-gamma promoter activity from I kappa B zeta overexpression was confirmed by luciferase reporter assay. Finally, I kappa B zeta coprecipitated with p65 and p50 NF-kappa B in NK cells in response to IL-12/IL-18, suggesting that I kappa B zeta's effects on IFN-gamma promoter activity are coregulated by NF-kappa B. These results suggest that I kappa B zeta functions as an important regulator of IFN-gamma in human NK cells, further expanding the class of I kappa B zeta-modulated genes. (Blood. 2011; 117(10): 2855-2863)