Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase.
Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase.
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DOI：
10.1016/j.freeradbiomed.2006.07.016
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发表时间：
2006-11
影响因子：
7.4
通讯作者：
M. Sury;M. Frese‐Schaper;M. Mühlemann;F. Schulthess;I. Blasig;M. Täuber;S. Shaw;Stephan Christen
中科院分区：
文献类型：
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作者：
M. Sury;M. Frese‐Schaper;M. Mühlemann;F. Schulthess;I. Blasig;M. Täuber;S. Shaw;Stephan Christen
n -乙酰半胱氨酸（NAC）对细菌性脑膜炎等急性脑损伤动物模型具有神经保护作用。然而，NAC发挥神经保护作用的机制尚不清楚。急性脑损伤时，内皮素-1 （ET-1）基因表达受活性氧的部分调控，是NAC治疗的潜在靶点。因此，我们检测了NAC对肿瘤坏死因子(TNF)-α-诱导的脑血管内皮细胞产生ET-1的影响。NAC剂量依赖性地抑制TNF-α-诱导的pre - prot -1 mRNA上调和ET-1蛋白分泌，而诱导型一氧化氮合酶（iNOS）上调不受影响。有趣的是，NAC对TNF-α对NF-κB的初始激活（即i -κB降解、核p65易位和Ser536磷酸化）没有影响。然而，对NF-κB DNA结合的短暂抑制表明，NAC可能通过抑制NF-κB介导的ET-1基因表达完全转录激活所必需的平行通路来抑制ET-1的上调。与NAC类似，MEK1/2抑制剂U0126、p38抑制剂SB203580和蛋白激酶抑制剂H-89选择性抑制ET-1上调，而不影响核p65易位，表明NAC通过抑制丝裂原和应激激活蛋白激酶（MSK）抑制ET-1上调。支持这一观点的是，与NAC共处理抑制了TNF-α-诱导的MSK1和MSK2激酶活性的升高，而siRNA敲除实验表明，MSK2是参与TNF-α-诱导的ET-1上调的主要亚型。
N-Acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-α-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-α-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IκB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-κB by TNF-α. However, transient inhibition of NF-κB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-κB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-α-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-α-induced ET-1 upregulation.