Nitric oxide suppresses IL-8 transcription by inhibiting C-Jun N-terminal kinase-induced AP-1 activation
Nitric oxide suppresses IL-8 transcription by inhibiting C-Jun N-terminal kinase-induced AP-1 activation
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DOI：
10.1006/excr.2001.5218
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发表时间：
2001-06-10
影响因子：
3.7
通讯作者：
Fowler, AA
中科院分区：
文献类型：
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作者：
Natarajan, R;Gupta, S;Fowler, AA
评估激活蛋白-1（AP-1）在肿瘤坏死因子-α（TNF-α）诱导的白细胞介素-8（IL-8）基因表达中的作用。我们发现TNF-α通过瞬时转染IL-8启动子构建体pGL-3BF激活转化内皮细胞系ECV 304中的AP-1（2）。IL-8启动子上AP-1位点或NF-IL-6位点的突变抑制了TNF-α诱导的激活，表明这些转录因子与转录因子NF-κ B之间的合作。c-Jun显性负突变体的过表达抑制了TNF-α刺激后AP-1驱动的IL-8启动子的转录，表明AP-1和NF-κ B之间的协同相互作用对TNF-α存在下的IL-8转录至关重要。我们还表明，一氧化氮（NO），在一个外源性NO供体的形式，抑制AP-1亚基，c-Jun，通过下调c-Jun NH 2末端激酶的激活水平。这种下调可能是NO介导的抑制活化内皮细胞IL-8分泌的假定作用机制。这些观察结果首次表明，NO对激活的内皮细胞中的各种促炎效应物具有广泛的抑制活性。(C)北京：科学出版社.
The role of activator protein-1 (AP-1) in tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-8 (IL-8) gene expression was evaluated. We showed that TNF-alpha activates AP-1 in the transformed endothelial cell line ECV304 by transient transfections of IL-8 promoter construct pGL-3BF(2). Mutation of either the AP-1 site or the NF-IL-6 site on the IL-8 promoter suppressed the TNF-alpha -induced activation, suggesting cooperation between these transcription factors and transcription factor NF-kappaB. Overexpression of dominant negative mutants of c-Jun suppressed AP-1-driven transcription of the IL-8 promoter following stimulation by TNF-alpha, suggesting that cooperative interaction between AP-1 and NF-kappaB is essential for IL-8 transcription in the presence of TNF-alpha. We also showed that nitric oxide (NO), in the form of an exogenous NO donor, suppressed the level of activation of the AP-1 subunit, c-Jun, by down-regulation of c-Jun NH2 terminal kinase. This down-regulation could be the putative mechanism of action for NO-mediated inhibition of IL-8 secretion in activated endothelium. These observations suggest for the first time that NO has broad suppressive activities on various proinflammatory effecters in activated endothelium. (C) 2001 Academic Press.