Tumor necrosis factor-α mRNA remains unstable and hypoadenylated upon stimulation of macrophages by lipopolysaccharides
Tumor necrosis factor-α mRNA remains unstable and hypoadenylated upon stimulation of macrophages by lipopolysaccharides
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DOI：
10.1046/j.1432-1327.2000.01676.x
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发表时间：
2000-10-01
期刊：
影响因子：
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通讯作者：
Kruys, V
中科院分区：
文献类型：
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作者：
Mijatovic, T;Houzet, L;Kruys, V
在小鼠巨噬细胞中，TNF-α基因表达在转录和转录后水平受到调节。TNF-α mRNA的转录后调控是由位于3'非翻译区（UTR）的富含AU的元件（ARE）介导的，它控制TNF-α mRNA的翻译和稳定性。在静息巨噬细胞中，ARE抑制TNF-α mRNA翻译。用各种试剂[例如脂多糖（LPS）、病毒]激活巨噬细胞导致翻译去抑制，导致高水平TNF-α的产生。TNF-α ARE还显示赋予mRNA不稳定性，因为其从小鼠基因组中的缺失导致TNF-α mRNA半衰期增加[Kontoyiannis，D.，Pasparakis，M.，Pizzaro，T.，Cominelli，F. & Kollias，G.（1999）Immunity 10，387-398]。在这项研究中，我们测量了LPS激活巨噬细胞过程中TNF-α mRNA的半衰期以及poly（A）尾长。我们报告说，TNF-α mRNA是短暂的，即使在最大的TNF-α合成的条件。此外，TNF-α mRNA以组成性方式低腺苷酸化。这些结果表明，TNF-α mRNA的快速周转并不构成巨噬细胞中TNF-α生物合成的调节步骤，并且LPS刺激后TNF-α mRNA的翻译激活并不伴随着poly（A）尾长的变化。
TNF-alpha gene expression is regulated at transcriptional and post-transcriptional levels in mouse macrophages. The post-transcriptional regulation is mediated by the AU-rich element (ARE) located in the TNF-alpha mRNA 3' untranslated region (UTR), which controls its translation and stability. In resting macrophages, the ARE represses TNF-alpha mRNA translation. Activation of macrophages with various agents [for example lipopolysaccharide (LPS), viruses] results in translational derepression, leading to the production of high levels of TNF-alpha. TNF-alpha ARE has also been shown to confer mRNA instability as its deletion from the mouse genome leads to and increase in the TNF-alpha mRNA half-life [Kontoyiannis, D., Pasparakis, M., Pizzaro, T., Cominelli, F. & Kollias, G. (1999) Immunity 10, 387-398]. In this study, we measured the half-life as well as the poly(A) tail length of TNF-alpha mRNA in the course of macrophage activation by LPS. We report that TNF-alpha mRNA is short lived even in conditions of maximal TNF-alpha synthesis. Moreover, TNF-alpha mRNA is hypoadenylated in a constitutive manner. These results reveal that TNF-alpha mRNA rapid turnover does not constitute a regulatory step of TNF-alpha biosynthesis in macrophages and that TNF-alpha mRNA translational activation upon LPS stimulation is not accompanied by a change of poly(A) tail length.