β-elemene attenuates macrophage activation and proinflammatory factor production via crosstalk with Wnt/β-catenin signaling pathway
β-elemene attenuates macrophage activation and proinflammatory factor production via crosstalk with Wnt/β-catenin signaling pathway
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DOI：
10.1016/j.fitote.2017.10.015
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发表时间：
2018-01-01
期刊：
影响因子：
3.4
通讯作者：
Zhang, Hang
中科院分区：
文献类型：
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作者：
Fang, Yangyi;Kang, Yanhua;Zhang, Hang
β-榄香烯是从莪术中提取的一种具有抗肿瘤活性的传统药物。然而，β-榄香烯在炎症性疾病中的作用尚未确定。本研究旨在探讨β-榄香烯对脂多糖（LPS）诱导的小鼠巨噬细胞RAW 264. 7的抗炎作用及其可能的分子机制。我们发现β-榄香烯以剂量依赖的方式显著抑制LPS诱导的RAW264.7巨噬细胞系产生促炎介质，包括白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1 β）。β-榄香烯抑制LPS诱导的RAW 264. 7表达一氧化氮合酶（iNOS）和白细胞介素-10（IL-10），这与下调Wnt/β-catenin信号通路有关。重要的是，这项研究表明β-连环蛋白被β-榄香烯显著抑制，这似乎是Wnt/β-连环蛋白信号通路下调的主要原因。因此，原代巨噬细胞中β-连环蛋白的缺失逆转了β-连环蛋白引起的免疫应答抑制。此外，α-蛇麻烯（β-榄香烯的一种异构倍半萜烯）还能显著抑制LPS诱导的RAW 264. 7细胞β-catenin表达和Wnt/β-catenin信号通路。还发现α-蛇麻烯显著抑制LPS诱导的促炎细胞因子的产生。然而，α-蛇麻烯比β-榄香烯表现出更强的细胞毒性。总之，我们的数据表明，β-榄香烯通过β-连环蛋白的失活对促炎介质和细胞因子的产生有效的抑制作用，并且还证明了β-榄香烯在内毒素诱导的炎症中的保护作用。β-榄香烯可以作为潜在的无毒调节剂用于预防和治疗炎性疾病。
beta-elemene, extracted from Rhizoma zedoariae, has been widely used as a traditional medicine for its antitumor activity against a broad range of cancers. However, the effect of beta-elemene in inflammation disorders has yet to be determined. The present study was designed to investigate the anti-inflammatory effects and potential molecular mechanisms of beta-elemene in lipopolysaccharide (LPS)-induced murine macrophage cells RAW264.7. We found that the production of pro-inflammatory mediators, including interleukin-6(IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), induced by LPS was significantly suppressed by beta-elemene in a dose-dependent manner in RAW264.7 macrophage cell line. Also, beta-elemene inhibited LPS-induced nitric oxide synthase (iNOS) and interleukin-10 (IL-10) expression by RAW264.7, which was related to the down-regulation of Wnt/beta-catenin signaling pathway. Importantly, this study demonstrates that beta-catenin was significantly inhibited by beta-elemene, which appeared to be largely responsible for the down-regulation of Wnt/beta-catenin signaling pathway. Accordingly, the deletion of beta-catenin in primary macrophages reversed beta-catenin-elicited inhibition of immune response. Furthermore, beta-catenin expression and Wnt/beta-catenin signaling pathway induced by LPS in RAW264.7 was also significantly inhibited by alpha-humulene, one isomeric sesquiterpene of beta-elemene. alpha-humulene was also found to significantly inhibit LPS-induced production of proinflammatory cytokines. However, alpha-humulene showed more cytotoxic ability than beta-elemene. Collectively, our data illustrated that beta-elemene exerted a potent inhibitory effect on pro-inflammatory meditator and cytokines production via the inactivation of beta-catenin, and also demonstrated the protective functions of beta-elemene in endotoxin-induced inflammation. beta-elemene may serve as potential nontoxic modulatory agents for the prevention and treatment of inflammatory diseases.