Department of Microbiology and Immunology, National Chiayi University, Chiayi, Taiwan.
Toxicol Appl Pharmacol. 2010 May 15;245(1):21-35. doi: 10.1016/j.taap.2010.01.003. Epub 2010 Jan 29.
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 TNFalpha-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 IkappaBalpha 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 TNFalpha-treated ECs, NF-kappaB 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 TNFalpha-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.
单核细胞与受损内皮层的黏附增加是动脉粥样硬化形成的一个关键早期事件。在炎症条件下，激活的血管内皮细胞上表达特定的细胞黏附分子增加，从而增加单核细胞的黏附。在我们目前的研究中，我们证明了迷迭香衍生的二萜化合物 carnosol 具有抗炎作用的一种可能机制。我们的结果表明，carnosol 和迷迭香油都能抑制 TNFalpha 诱导的单核细胞与内皮细胞的黏附，并在转录水平上抑制 ICAM-1 的表达。此外，carnosol 通过阻断短期预处理中抑制蛋白 IkappaBalpha 的降解来发挥其抑制作用，但在 12 小时预处理中则不会。我们的数据表明，carnosol 在预处理时间少于 3 小时内可减少 IKK-beta 的磷酸化。在 TNFalpha 处理的 ECs 中，NF-kappaB 核转位和转录活性在 carnosol 预处理 12 小时内被完全阻断，而这一过程被 Nrf-2 siRNA 阻断。carnosol 的长期抑制作用似乎是通过诱导 Nrf-2 相关基因来介导的。HO-1 siRNA 逆转了 ICAM-1 表达和 p65 易位的抑制。carnosol 还上调了 Nrf-2 相关的谷胱甘肽合酶基因，从而在暴露 9 小时后增加 GSH 水平。用 GSH 合成抑制剂 BSO 处理 ECs，可阻断 carnosol 的抑制作用。此外，carnosol 增加了 p65 的谷胱甘肽化。因此，我们目前的研究结果表明，carnosol 通过抑制 IKK-beta 活性或上调 HO-1 表达来抑制 TNFalpha 诱导的信号通路。然而，GSH 水平的增加取决于 carnosol 预处理时间的长短。
