IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-γ expression in murine NK cells
IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-γ expression in murine NK cells
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DOI：
10.1182/blood-2002-08-2602
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发表时间：
2003-07-01
期刊：
影响因子：
20.3
通讯作者：
Young, HA
中科院分区：
文献类型：
--
作者：
Bream, JH;Curiel, RE;Young, HA
白介素4(IL-4)被认为通过下调辅助性T细胞(Th1)类细胞因子，如干扰素-γ(IFN-Gamma)来影响T细胞和自然杀伤(NK)细胞。在研究IL-4对干扰素-γ表达的调节时，我们发现IL-4与IL-2或IL-12协同作用，促进脾来源、IL-2培养的NK细胞的干扰素-γ的产生和mRNA的表达，以及负向分选新鲜的DX5(+)/CD3(-)NK细胞，尽管水平较低。IL-4对IL-2诱导的干扰素-γ产生的积极作用依赖于信号转导和转录激活因子6(Stat6)，因为这一反应在Stat6(-/-)小鼠中几乎被取消。然而，值得注意的是，在Stat6(-/-)小鼠中，IL-12和IL-4对干扰素-γ表达的协同作用是完整的。在探索IL-4对小鼠NK细胞协同作用的可能分子机制中，我们发现IL-2和IL-4刺激导致Stat5酪氨酸磷酸化的轻微增加，而IL-12和IL-4处理导致更显著的酪氨酸磷酸化的STAT4的增加。最后，为了确定可能涉及干扰素-γ启动子的区域，用细胞因子处理来自人干扰素-γ启动子/荧光素酶转基因小鼠的NK细胞。近端(-110to+)启动子区域的小鼠NK细胞对细胞因子刺激无反应，而完整启动子-565to+对NK细胞中IL-2+IL-4和IL-12+IL-4有协同作用。这些数据表明，在IL-2共刺激中，IL-4部分依赖于Stat6，在IL-12共刺激中完全不依赖于Stat6，而在小鼠NK细胞中，IL-4在促进干扰素-γ的表达中起作用。(C)2003年，由美国血液病学会提供。
Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)-type cytokines like interferon-gamma (IFN-gamma). While investigating IL-4 regulation of IFN-gamma expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-gamma production and mRNA expression in spleen-derived, IL-2-cultured NK cells, as well as negatively sorted fresh DX5(+)/CD3(-) NK cells albeit at lower levels. The positive effect of IL-4 on IL-2-induced IFN-gamma production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6(-/-) mice. Notably, though, IL-12 plus IL-4 synergy on IFN-gamma expression was intact in Stat6(-/-) mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-gamma promoter that may be involved, NK cells from human IFN-gamma promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-gamma promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-gamma expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations. (C) 2003 by The American Society of Hematology.