Inhibition of lipopolysaccharide-induced cyclooxygenase-2 transcription by 6-(methylsulfinyl) hexyl isothiocyanate, a chemopreventive compound from Wasabia japonica (Miq.) Matsumura, in mouse macrophages
Inhibition of lipopolysaccharide-induced cyclooxygenase-2 transcription by 6-(methylsulfinyl) hexyl isothiocyanate, a chemopreventive compound from Wasabia japonica (Miq.) Matsumura, in mouse macrophages
复制标题
DOI：
10.1016/j.bcp.2005.09.023
复制
发表时间：
2005-12-05
影响因子：
5.8
通讯作者：
Hou, DX
中科院分区：
文献类型：
--
作者：
Uto, T;Fujii, M;Hou, DX
6-（甲基亚硫酰基）己基异硫氰酸酯（6- mitc）是发生在山葵（Wasabia japonica (Miq.)）中的化学预防化合物。松村)，这是一种在日本非常受欢迎的辛辣香料。我们研究了6-MITC对脂多糖（LPS）激活的小鼠巨噬细胞RAW264细胞中环氧合酶-2 （COX-2）表达的影响。6-MITC以剂量依赖的方式抑制lps介导的COX-2蛋白诱导。不同COX-2启动子报告基因构建的转染结果表明，6-MITC对COX-2基因表达的抑制作用是由核心启动子元件包括核因子κ B （nf - κ B）、CCAAT/增强子结合蛋白（C/EBP）和环amp反应元件（CRE）位点指导的。Western blotting分析显示，6-MITC抑制了lps诱导的MAPK （ERK、p38激酶和JNK）和转录因子（CREB、C - jun和C/EBP delta）结合COX-2启动子核心元件的激活，证实了6-MITC参与了这些信号转导途径对COX-2表达的调控。此外，使用mapk特异性抑制剂（MEK1/2的U0126， p38激酶的SB203580和JNK的SP600125）进行的Western blotting实验表明，6-MITC通过阻断JNK介导的AP-1和ERK/p38激酶介导的CREB或C/EBP δ的激活来抑制lps诱导的COX-2表达。最后，结构活性研究表明，甲基亚砜基异硫氰酸酯（MITCs）的抑制效能与甲基链长度有关。这些发现首次证明了6-MITC是一种有效的减少COX-2产生的药物，并加深了我们对6-MITC抗炎症特性的理解。(c) 2005爱思唯尔公司版权所有。
6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC) is a chemopreventive compound occurring in Wasabi (Wasabia japonica (Miq.) Matsumura), which is a very popular pungent spice in Japan. We investigated the effects of 6-MITC on the expression of cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. Treatment with 6-MITC suppressed LPS-mediated induction of COX-2 protein in a dose-dependent manner. Transfections with various COX-2 promoter reporter constructs revealed that the inhibitory effects of 6-MITC on COX-2 gene expression were directed by the core promoter elements including nuclear factor kappa B (NF-kappa B), CCAAT/enhancer-binding protein (C/EBP) and cyclic AMP-response element (CRE) sites. Western blotting analysis showed that 6-MITC inhibited LPS-induced activation of MAPK (ERK, p38 kinase and JNK) and transcriptional factors (CREB, c-Jun and C/EBP delta) binding the core elements of COX-2 promoter, substantiating the involvement of these signal transduction pathways in the regulation of COX-2 expression by 6-MITC. Moreover, Western blotting experiments with MAPK-specific inhibitors (U0126 for MEK1/2, SB203580 for p38 kinase and SP600125 for JNK) demonstrated that 6-MITC suppressed LPS-induced COX-2 expression by blocking the activation of JNK-mediated AP-1 and ERK/p38 kinase-mediated CREB or C/EBP delta. Finally, the structure-activity study revealed that the inhibitory potency of methylsulfinyl isothiocyanates (MITCs) depended on the methyl chain length. These findings demonstrate-for the first time that 6-MITC is an effective agent to attenuate COX-2 production, and enhance our understanding of the anti-inflammation properties of 6-MITC. (c) 2005 Elsevier Inc. All rights reserved.