TRANSCRIPTIONAL REGULATION OF THE ENDOTHELIN-1 GENE BY TNF-ALPHA
TRANSCRIPTIONAL REGULATION OF THE ENDOTHELIN-1 GENE BY TNF-ALPHA
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DOI：
10.1152/ajpcell.1992.262.4.c854
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发表时间：
1992-04-01
影响因子：
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通讯作者：
BRENNER, BM
中科院分区：
文献类型：
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作者：
MARSDEN, PA;BRENNER, BM
细胞因子，如肿瘤坏死因子-α（TNF-α），诱导内皮细胞表型的深刻变化，并涉及器官功能障碍，特征是脓毒性休克。 我们探讨了TNF-α是否调节内皮素-1（ET-1）的细胞表达。 ET-1是一种由内皮细胞、血管平滑肌细胞和系膜细胞释放的有效缩血管肽，可作为血管张力和增殖的旁分泌/自分泌调节剂发挥作用。 我们发现，TNF-α诱导牛主动脉内皮细胞（BAEC）释放ET-1的时间和浓度依赖性的方式。 ET-1释放速率在1-8小时内最大，16小时后降至或低于基线值。 当在8小时测量时，TNF-α在0.1-250 ng/ml范围内增加ET-1释放（阈值，0.1 ng/ml; 50%有效剂量，1.6 +/- 1.2 ng/ml;最大效应，100 ng/ml）。 分泌的增加伴随着ET-1基因的转录速率的相应增加，导致增强的前内皮素原-1 mRNA转录水平。 TNF-α刺激的ET-1基因转录增加不依赖于新蛋白质的合成。 放线菌素D追踪实验表明，前内皮素原-1 mRNA的稳定性增强不能解释ET-1转录水平的增加。 TNF-α增加了牛肾动脉和牛肾小球毛细血管内皮细胞中ET-1的释放和前内皮素原-1 mRNA的含量，表明TNF-α的作用在各种来源的内皮细胞中是明显的。 此外，牛肾小球系膜细胞对TNF-α的反应中ET-1的表达明显增加。 血管床中ET-1的产生增强可能遵循细胞因子激活，并有助于在感染性休克中观察到的器官功能障碍。
Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), induce profound alterations in endothelial cell phenotype and are implicated in the organ dysfunction that characterizes septic shock. We explored whether TNF-alpha modulates cellular expression of endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor peptide released by endothelial, vascular smooth muscle, and mesangial cells that could function as a paracrine/autocrine regulator of vascular tone and proliferation. We found that TNF-alpha induced release of ET-1 from bovine aortic endothelial cells (BAEC) in a time- and concentration-dependent manner. Rates of ET-1 release were maximal over 1-8 h and declined to, or below, baseline values after 16 h. When measured at 8 h, TNF-alpha augmented ET-1 release over the range 0.1-250 ng/ml (threshold, 0.1 ng/ml; 50% effective dose, 1.6 +/- 1.2 ng/ml; maximal effect, 100 ng/ml). The increase in secretion was accompanied by a corresponding increase in the transcriptional rate of the ET-1 gene resulting in augmented preproendothelin-1 mRNA transcript levels. TNF-alpha-stimulated increases in ET-1 gene transcription were not dependent on new protein synthesis. Actinomycin D chase experiments suggested that enhanced stability of preproedothelin-1 mRNA could not account for the increase in ET-1 transcript levels. TNF-alpha increased ET-1 release and preproendothelin-1 mRNA content in bovine renal artery and bovine glomerular capillary endothelial cells, demonstrating that the TNF-alpha effect was evident in endothelial cells derived from a variety of sources. Furthermore, augmented ET-1 expression in response to TNF-alpha was evident in bovine glomerular mesangial cells. Enhanced production of ET-1 in vascular beds may follow cytokine activation and contribute to the organ dysfunction observed in septic shock.