IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12.
IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12.
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发表时间：
2001
影响因子：
5.4
通讯作者：
S. Matikainen;A. Paananen;M. Miettinen;M. Kurimoto;T. Timonen;I. Julkunen;T. Sareneva
中科院分区：
文献类型：
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作者：
S. Matikainen;A. Paananen;M. Miettinen;M. Kurimoto;T. Timonen;I. Julkunen;T. Sareneva
干扰素-γ是NK细胞和T细胞的产物，是天然免疫和获得性免疫的关键细胞因子。干扰素-γ的产生是通过细胞间直接接触APC和产生干扰素的细胞或由细胞因子诱导的。在微生物感染期间，巨噬细胞来源的干扰素-α、IL-12和IL-18可促进干扰素-γ的产生和Th1反应。在这里，我们表明，干扰素-α与IL-18联合非常有效地诱导原代、未激活的NK细胞和NK-92细胞系表达干扰素-γ。比较未激活的NK细胞、NK-92细胞和激活的T细胞在干扰素-α和IL-12刺激下的表达动力学发现，虽然这两种细胞因子都直接上调了干扰素-γ的表达，但其水平在IL-12刺激下持续升高的时间更长。已知在NK细胞和T细胞中，STAT4在IL-12和干扰素-α信号转导中起关键作用。我们发现，在干扰素-α刺激的细胞中，STAT4的激活是暂时的，而IL-12诱导了更持久的转录因子激活。与干扰素-α相比，IL-12对干扰素-γ基因的长时间激活可能会导致更有效的干扰素-γ的产生。我们的结果表明，干扰素-α和IL-18是诱导NK细胞产生干扰素-γ的重要先天细胞因子。
IFN-gamma, a product of NK and T cells, is a key cytokine contributing innate and adaptive immunity. IFN-gamma production is induced via direct cell-cell contacts with APC and IFN-gamma -producing cells or by cytokines. During microbial infections macrophage-derived IFN-alpha, IL-12, and IL-18 enhance IFN-gamma production and Th1 response. Here we show that IFN-alpha in combination with IL-18 very efficiently induces IFN-gamma expression also in primary, nonactivated NK cells and in NK-92 cell line. Comparison of the kinetics of IFN-gamma mRNA expression in nonactivated NK cells, NK-92 cells and activated T cells stimulated with IFN-alpha or IL-12 revealed that, although both of these cytokines directly up-regulate IFN-gamma mRNA expression, its levels remain elevated much longer with IL-12 stimulation. In both NK cells and T cells, Stat4 is known to be critical in IL-12 and IFN-alpha signaling. We show that Stat4 activation is transient in cells stimulated with IFN-alpha, whereas IL-12 induces more long-lasting activation of the transcription factor. This prolonged activation of IFN-gamma gene by IL-12 may result in more efficient IFN-gamma production compared to that of IFN-alpha. Our results demonstrate that IFN-alpha and IL-18 are important innate cytokines in inducing NK cell IFN-gamma production.