Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc.
Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc.
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DOI：
10.3892/ijmm_00000172
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发表时间：
2009-05-01
影响因子：
5.4
通讯作者：
Maruyama, Ikuro
中科院分区：
文献类型：
--
作者：
Kawahara, Ko-Ichi;Hashiguchi, Teruto;Maruyama, Ikuro
主要来自细胞核的高迁移率族蛋白B1（HMGB 1）被动地从坏死细胞或通过单核细胞/巨噬细胞的分泌主动地释放到细胞外环境中。细胞外HMGB 1通过促进细胞因子如肿瘤坏死因子（TNF）-α的释放而充当有效的炎症剂，具有促凝血活性，并参与败血症所致的死亡。因此，HMGB 1是合适的治疗靶点。在这项研究中，我们发现，梅提取物Sieb。et Zucc. (Ume)果实（乌梅提取物）是三萜类化合物的丰富来源，强烈抑制脂多糖（LPS）刺激的巨噬细胞样RAW 264.7细胞的HMGB 1释放。对HMGB 1释放的抑制作用通过真实的油酸（OA）（一种天然存在的三萜类化合物）增强。类似地，发现乌梅提取物中的HMGB 1释放抑制剂是OA。关于HMGB 1释放的抑制机制，发现OA或乌梅提取物激活转录因子Nrf 2，其结合到抗氧化反应元件，随后诱导血红素加氧酶（HO）-1蛋白，表明HMGB 1从LPS刺激的RAW 264.7细胞释放的抑制是通过Nrf 2/HO-1系统介导的;基本上是抗氧化作用。这些结果表明，天然来源的三萜类化合物值得进一步评估作为败血症和其他潜在致命的全身性炎症性疾病的“救援”治疗。
High mobility group box-1 protein (HMGB1), primarily from the nucleus, is released into the extracellular milieu either passively from necrotic cells or actively through secretion by monocytes/macrophages. Extracellular HMGB1 acts as a potent inflammatory agent by promoting the release of cytokines such as tumor necrosis factor (TNF)-alpha, has procoagulant activity, and is involved in death due to sepsis. Accordingly, HMGB1 is an appropriate therapeutic target. In this study, we found that an extract of Prunus mume Sieb. et Zucc. (Ume) fruit (Ume extract), an abundant source of triterpenoids, strongly inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. The inhibitory effect on HMGB1 release was enhanced by authentic oleanolic acid (OA), a naturally occurring triterpenoid. Similarly, the HMGB1 release inhibitor in Ume extract was found to be OA. Regarding the mechanisms of the inhibition of HMGB1 release, the OA or Ume extract was found to activate the transcription factor Nrf2, which binds to the antioxidative responsive element, and subsequently the heme oxygenase (HO)-1 protein was induced, indicating that the inhibition of HMGB1 release from LPS-stimulated RAW264.7 cells was mediated via the Nrf2/HO-1 system; an essentially antioxidant effect. These results suggested that natural sources of triterpenoids warrant further evaluation as 'rescue' therapeutics for sepsis and other potentially fatal systemic inflammatory disorders.