Regulation of nuclear gamma interferon gene expression by interleukin 12 (IL-12) and IL-2 represents a novel form of posttranscriptional control
Regulation of nuclear gamma interferon gene expression by interleukin 12 (IL-12) and IL-2 represents a novel form of posttranscriptional control
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DOI：
10.1128/mcb.22.6.1742-1753.2002
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发表时间：
2002-03-01
影响因子：
5.3
通讯作者：
Young, HA
中科院分区：
文献类型：
--
作者：
Hodge, DL;Martinez, A;Young, HA
γ-干扰素（IFN-γ）基因表达的转录后调控尚未得到广泛研究，也知之甚少。我们的工作描述了一种转录后机制，通过IFN-γ mRNA的核滞留来调节受刺激的自然杀伤（NK）细胞中IFN-γ mRNA的表达。这通过在用白介素-12（IL-12）刺激的NK细胞中前体和加工的IFN-γ mRNA的升高和持续的核积累来证明。在转录活性消退且细胞质IFN-γ mRNA积累速率下降后，核mRNA积累的升高持续很长时间。IL-12诱导的IFN-γ mRNA的核滞留占优势，直到接收到二次细胞因子刺激。由IL-2启动的次级刺激介导核IFN-γ mRNA的转录非依赖性运动。与IFN-γ mRNA的核质运动同时，我们观察到加工的核IFN-γ mRNA的量增加，其大于未加工的IFN-γ mRNA的量。经加工的IFN-γ mRNA的增加似乎是由于mRNA稳定性增加，其随后促进成熟IFN-γ mRNA的核质穿梭增加。这些数据支持这样一种模型，即细胞核IFN-γ mRNA库的动员允许NK细胞以不依赖于转录的方式快速且稳健地响应于次级细胞因子激活剂，从而缩短了对炎症信号的总体细胞响应的时间。
Posttranscriptional control of gamma interferon (IFN-gamma) gene expression has not been extensively studied and is poorly understood. Our work describes a posttranscriptional mechanism that modulates IFN-gamma mRNA expression in stimulated natural killer (NK) cells through nuclear retention of the IFN-gamma mRNA. This is evidenced by the elevated and sustained nuclear accumulation of both precursor and processed IFN-gamma mRNAs in NK cells stimulated with interleukin-12 (IL-12). The elevated nuclear mRNA accumulation persists long after transcriptional activity has subsided and the rate of cytoplasmic IFN-gamma mRNA accumulation has dropped. The IL-12-induced nuclear retention of the IFN-gamma mRNA prevails until a secondary cytokine stimulus is received. The secondary stimulus, which is initiated by IL-2, mediates transcription-independent movement of the nuclear IFN-gamma mRNA. Concurrent with the nucleocytoplasmic movement of the IFN-gamma mRNA, we have observed increases in the amount of processed nuclear IFN-gamma mRNA that are greater than that seen for the unprocessed IFN-gamma mRNA. The increase in processed IFN-gamma mRNA appears to be due to increased mRNA stability which then promotes increased nucleocytoplasmic shuttling of the mature IFN-gamma mRNA. These data support a model whereby mobilization of nuclear IFN-gamma mRNA stores allows NK cells to rapidly and robustly respond to secondary cytokine activators in a transcription-independent manner, thus shortening the time for overall cellular response to inflammatory signals.