Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: Structure-activity relationship and molecular mechanisms involved
Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: Structure-activity relationship and molecular mechanisms involved
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DOI：
10.1016/j.bcp.2005.05.003
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发表时间：
2005-08-01
影响因子：
5.8
通讯作者：
Fujii, M
中科院分区：
文献类型：
--
作者：
Hou, DX;Yanagita, T;Fujii, M
以脂多糖（lipopolysaccharide，LPS）激活的小鼠巨噬细胞RAW 264为模型，研究了花色苷（anthocyanidins）对环氧化酶2（cyclooxygenase-2，考克斯-2）表达的影响。在5种花青素中，飞燕草素和矢车菊素抑制LPS诱导的考克斯-2表达，而天竺葵素、芍药素和锦葵色素则无此作用。构效关系表明，花青素B环上的邻二羟基苯基结构可能与抑制作用有关。最有效的抑制剂Delphinidin在mRNA和蛋白水平上均引起考克斯-2表达的剂量依赖性抑制。Western blotting分析表明，飞燕草素可抑制I κ β-α的降解、p65和CCAAT/增强子结合蛋白（C/EBP）δ的核转位以及c-Jun的磷酸化，但对CREB无影响。此外，翠雀素还抑制c-Jun N末端激酶（JNK）、细胞外信号调节激酶（ERK）和p38激酶等促分裂原活化蛋白激酶（MAPK）的激活。MAPK抑制剂（用于MEK 1/2的U 0126、用于p38激酶的SB 203580和用于JNK的SP 600125）特异性阻断LPS诱导的考克斯-2表达。因此，我们的研究结果表明，LPS通过激活MAPK途径诱导考克斯-2表达，飞燕草素通过阻断MAPK介导的途径抑制考克斯-2表达，并伴随着核因子-κ B（NF-κ B）、激活蛋白（AP-1）和C/EBP δ的激活。这些发现为具有邻二羟基苯基结构的花青素可能通过抑制MAPK介导的考克斯-2表达而具有抗炎活性提供了第一个分子基础。(c)2005年爱思唯尔公司All rights reserved.
The effects of anthocyanidins, the aglycon nucleuses of anthocyanins widely occurring in reddish fruits and vegetables, on the expression of cyclooxygenase-2 (COX-2) were investigated in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. Of five anthocyanidins, delphinidin and cyanidin inhibited LPS-induced COX-2 expression, but pelargonidin, peonidin and malvidin did not. The structure-activity relationship suggest that the ortho-dihydroxyphenyl structure of anthocyanidins on the B-ring appears to be related with the inhibitory actions. Delphinidin, the most potent inhibitor, caused a dose-dependent inhibition of COX-2 expression at both mRNA and protein levels. Western blotting analysis indicated that delphinidin inhibited the degradation Of I kappa beta-alpha, nuclear translocation of p65 and CCAAT/enhancer-binding protein (C/EBP)delta and phosphorylation of c-Jun, but not CRE-binding protein (CREB). Moreover, delphinidin suppressed the activations of mitogen-activated protein kinase (MAPK) including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 kinase. MAPK inhibitors (U0126 for MEK1/2, SB203580 for p38 kinase, and SP600125 for JNK) specifically blocked LPS-induced COX-2 expression. Thus, our results demonstrated that LPS-induced COX-2 expression by activating MAPK pathways and delphinidin suppressed COX-2 by blocking MAPK-mediated pathways with the attendant activation of nuclear factor-kappa B (NF-kappa B), activator protein-] (AP-1) and C/EBP delta. These findings provide the first molecular basis that anthocyanidins with ortho-dihydroxyphenyl structure may have anti-inflammatory properties through the inhibition of MAPK-mediated COX-2 expression. (c) 2005 Elsevier Inc. All rights reserved.