Dual mechanisms of NF-κB inhibition in carnosol-treated endothelial cells
Dual mechanisms of NF-κB inhibition in carnosol-treated endothelial cells
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DOI：
10.1016/j.taap.2010.01.003
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发表时间：
2010-05-15
影响因子：
3.8
通讯作者：
Sun, Yung-Wei
中科院分区：
文献类型：
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作者：
Lian, Kai-Cheng;Chuang, Jing-Jing;Sun, Yung-Wei
单核细胞粘附损伤内皮层的增加是动脉粥样硬化发生的关键早期事件。在炎症条件下，激活的血管内皮细胞上特异性细胞粘附分子的表达增加，从而增加单核细胞粘附。在我们目前的研究中，我们证明了鼠尾草醇（一种从草药迷迭香中提取的二萜）抗炎作用的假定机制。我们的研究结果表明，鼠尾草醇和迷迭香精油都能抑制TNF α诱导的单核细胞对内皮细胞的粘附，并在转录水平上抑制ICAM-1的表达。此外，研究发现，鼠油醇通过阻断抑制蛋白I κ pa B α的降解，在短期预处理中发挥抑制作用，而在预处理12 h时则不起作用。我们的数据显示，在预处理不到3小时的情况下，鼠油醇降低了ikk - β的磷酸化。在TNF α处理的ec中，鼠油醇预处理12小时后，NF-kappa B核易位和转录活性被取消，这被Nrf-2 siRNA阻断。因此，鼠油醇的长期抑制作用似乎是通过诱导nrf -2相关基因介导的。HO-1 siRNA可逆转ICAM-1表达和p65易位的抑制作用。鼠油醇还能上调nrf -2相关谷胱甘肽合成酶基因，从而在暴露9小时后增加谷胱甘肽水平。用GSH合成抑制剂BSO处理ECs，可阻断肌醇的抑制作用。此外，鼠油醇增加p65谷胱甘肽化。因此，我们目前的研究结果表明，鼠油醇通过抑制ikk - β活性或上调HO-1表达来抑制tnfa诱导的单链通路。然而，由此产生的谷胱甘肽水平取决于鼠尾草醇预处理时间的长短。(C) 2010爱思唯尔公司版权所有。
The increased adhesion of monocytes to injured endothelial layers is a critical early event in atherogenesis. Under inflammatory conditions, there is increased expression of specific cell adhesion molecules on activated vascular endothelial cells, which increases monocyte adhesion. In our current study, we demonstrate a putative mechanism for the anti-inflammatory effects of carnosol, a diterpene derived from the herb rosemary. Our results show that both carnosol and rosemary essential oils inhibit the adhesion of TNF alpha-induced monocytes to endothelial cells and suppress the expression of ICAM-1 at the transcriptional level. Moreover, carnosol was found to exert its inhibitory effects by blocking the degradation of the inhibitory protein I kappa B alpha in short term pretreatments but not in 12 h pretreatments. Our data show that carnosol reduces IKK-beta phosphorylation in pretreatments of less than 3 h. In TNF alpha-treated ECs, NF-kappa B nuclear translocation and transcriptional activity was abolished by up to 12 h of carnosol pretreatment and this was blocked by Nrf-2 siRNA. The long-term inhibitory effects of carnosol thus appear to be mediated through its induction of Nrf-2-related genes. The inhibition of ICAM-1 expression and p65 translocation is reversed by HO-1 siRNA. Carnosol also upregulates the Nrf-2-related glutathione synthase gene and thereby increases the GSH levels after 9 h of exposure. Treating ECs with a GSH synthesis inhibitor, BSO, blocks the inhibitory effects of carnosol. In addition, carnosol increases p65 glutathionylation. Hence, our present findings indicate that carnosol suppresses TNFa-induced singling pathways through the inhibition of IKK-beta activity or the upregulation of HO-1 expression. The resulting GSH levels are dependent, however, on the length of the carnosol pretreatment period. (C) 2010 Elsevier Inc. All rights reserved.