MacKenzie Simon, Fernàndez-Troy Neus, Espel Enric
Dept. de Fisiologia, Facultat de Biologia, Universitat de Barcelona, Spain.
J Leukoc Biol. 2002 Jun;71(6):1026-32.
Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, is produced abundantly by monocytes and macrophages. We have compared LPS-stimulated TNF-alpha production and regulation in freshly isolated human monocytes and macrophages differentiated in vitro. A significant increase in LPS-induced TNF-alpha protein secretion was observed in macrophages over freshly isolated monocytes without comparable differences in TNF-alpha mRNA induction. Polysome gradient analysis showed polysome-mRNA distribution did not change, whereas TNF-alpha mRNA stability increased in macrophages. Tristetraprolin mRNA expression was constitutive and decreased with differentiation-linked kinetics. Blockable LPS-inducible MAP kinase activity (p38, ERK) affected TNF-alpha biosynthesis differentially at the transcriptional and post-transcriptional level throughout the culture period. We suggest that the increase in TNF-alpha secretion in macrophages relates to changes in post-transcriptional processing, which is regulated indirectly by the expression of RNA-binding proteins. Changes in gene expression throughout monocytic differentiation equip the cell to act as a more potent producer of this proinflammatory cytokine.
肿瘤坏死因子α（TNF-α）是一种促炎细胞因子，由单核细胞和巨噬细胞大量产生。我们比较了脂多糖（LPS）刺激下，新鲜分离的人单核细胞与体外分化的巨噬细胞中TNF-α的产生及调控情况。在巨噬细胞中，LPS诱导的TNF-α蛋白分泌相较于新鲜分离的单核细胞有显著增加，而TNF-α mRNA诱导方面无类似差异。多核糖体梯度分析显示，多核糖体-mRNA分布未改变，但巨噬细胞中TNF-α mRNA稳定性增加。锌指蛋白16 mRNA表达呈组成型，并随分化相关动力学而降低。可被阻断的LPS诱导的丝裂原活化蛋白激酶活性（p38、细胞外信号调节激酶）在整个培养期间，在转录和转录后水平对TNF-α生物合成有不同影响。我们认为，巨噬细胞中TNF-α分泌增加与转录后加工的变化有关，而转录后加工由RNA结合蛋白的表达间接调控。单核细胞分化过程中基因表达的变化使细胞成为这种促炎细胞因子更有效的产生者。
