Liao Being-Chyuan, Hsieh Chia-Wen, Liu Yen-Chin, Tzeng Tsai-Teng, Sun Yung-Wei, Wung Being-Sun
Department of Microbiology and Immunology, National Chiayi University, Chiayi, Taiwan.
Toxicol Appl Pharmacol. 2008 Jun 1;229(2):161-71. doi: 10.1016/j.taap.2008.01.021. Epub 2008 Feb 5.
The production of adhesion molecules and subsequent attachment of leukocytes to endothelial cells (ECs) are critical early events in atherogenesis. These adhesion molecules thus play an important role in the development of this disease. Recent studies have highlighted the chemoprotective and anti-inflammatory effects of cinnamaldehyde, a Cinnamomum cassia Presl-specific diterpene. In our current study, we have examined the effects of both cinnamaldehyde and extracts of C. cassia on cytokine-induced monocyte/human endothelial cell interactions. We find that these compounds inhibit the adhesion of TNFalpha-induced monocytes to endothelial cells and suppress the expression of the cell adhesion molecules, VCAM-1 and ICAM-1, at the transcriptional level. Moreover, in TNFalpha-treated ECs, the principal downstream signal of VCAM-1 and ICAM-1, NF-kappaB, was also found to be abolished in a time-dependent manner. Interestingly, cinnamaldehyde exerts its anti-inflammatory effects by blocking the degradation of the inhibitory protein IkappaB-alpha, but only in short term pretreatments, whereas it does so via the induction of Nrf2-related genes, including heme-oxygenase-1 (HO-1), over long term pretreatments. Treating ECs with zinc protoporphyrin, a HO-1 inhibitor, partially blocks the anti-inflammatory effects of cinnamaldehyde. Elevated HO-1 protein levels were associated with the inhibition of TNFalpha-induced ICAM-1 expression. In addition to HO-1, we also found that cinnamaldehyde can upregulate Nrf2 in nuclear extracts, and can increase ARE-luciferase activity and upregulate thioredoxin reductase-1, another Nrf2-related gene. Moreover, cinnamaldehyde exposure rapidly reduces the cellular GSH levels in ECs over short term treatments but increases these levels after 9 h exposure. Hence, our present findings indicate that cinnamaldehyde suppresses TNF-induced singling pathways via two distinct mechanisms that are activated by different pretreatment periods.
黏附分子的产生以及随后白细胞与内皮细胞（ECs）的附着是动脉粥样硬化形成过程中的关键早期事件。因此，这些黏附分子在该疾病的发展中起着重要作用。最近的研究强调了肉桂醛（一种肉桂特有的二萜）的化学保护和抗炎作用。在我们目前的研究中，我们研究了肉桂醛和肉桂提取物对细胞因子诱导的单核细胞/人内皮细胞相互作用的影响。我们发现这些化合物在转录水平上抑制肿瘤坏死因子α（TNFα）诱导的单核细胞与内皮细胞的黏附，并抑制细胞黏附分子血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）的表达。此外，在TNFα处理的内皮细胞中，还发现VCAM-1和ICAM-1的主要下游信号核因子κB（NF-κB）以时间依赖性方式被消除。有趣的是，肉桂醛通过阻断抑制蛋白IκB-α的降解发挥其抗炎作用，但仅在短期预处理中如此，而在长期预处理中，它是通过诱导包括血红素加氧酶-1（HO-1）在内的Nrf2相关基因来发挥作用。用HO-1抑制剂锌原卟啉处理内皮细胞可部分阻断肉桂醛的抗炎作用。HO-1蛋白水平升高与TNFα诱导的ICAM-1表达受到抑制有关。除了HO-1，我们还发现肉桂醛可以上调核提取物中的Nrf2，并可以增加抗氧化反应元件（ARE）荧光素酶活性，上调另一个Nrf2相关基因硫氧还蛋白还原酶-1。此外，在短期处理中，肉桂醛暴露会迅速降低内皮细胞中的细胞谷胱甘肽（GSH）水平，但在暴露9小时后会增加这些水平。因此，我们目前的研究结果表明，肉桂醛通过两种不同的机制抑制TNF诱导的信号通路，这两种机制由不同的预处理时间激活。
