To assess the potential role of daphnetin, a clinically used anti-inflammatory agent, on the development of the inflammatory and neurodegenerative disease, we investigated its immune regulatory function in a murine model of experimental autoimmune encephalomyelitis (EAE). Significantly, lower levels of pro-inflammatory cytokines including interleukin (IL)-17, interferon-γ, Il6, Il12a, and Il23a were observed in brains of daphnetin-treated EAE mice, compared with those in control littermates. We also confirmed that daphnetin suppressed the production of IL-1β, IL-6, and tumor necrosis factor-α in lipopolysaccharide-stimulated mouse BV2 microglial cells. Mechanistically, heme oxygenase-1 (HO-1), a canonical anti-oxidant and anti-inflammatory factor, was found to be substantially induced by daphnetin treatment in BV2 cells. Also, a significantly higher level of HO-1, accompanied by a decreased level of malondialdehyde, was observed in daphnetin-treated EAE mice. More importantly, the deletion of HO-1 in BV2 microglia largely abrogated daphnetin-mediated inhibition of the inflammatory response. Together, our data demonstrate that daphnetin has an anti-inflammatory and neuroprotective role during the pathogenesis of EAE, which is partially at least, dependent on its regulation of HO-1.

中文翻译：

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达芙妮通过调节血红素加氧酶-1改善实验性自身免疫性脑脊髓炎。

为了评估达芬肽（一种临床使用的消炎药）对炎症和神经退行性疾病发展的潜在作用，我们在实验性自身免疫性脑脊髓炎（EAE）的鼠模型中研究了其免疫调节功能。显着地，与对照组同窝出生的人相比，在用达啡肽治疗的EAE小鼠的大脑中观察到了较低的促炎细胞因子水平，包括白介素（IL）-17，干扰素-γ，Il6，Il12a和Il23a。我们还证实了蜂胶蛋白抑制了脂多糖刺激的小鼠BV2小胶质细胞中IL-1β，IL-6和肿瘤坏死因子-α的产生。从机理上讲，血红素加氧酶-1（HO-1）是一种典型的抗氧化剂和抗炎因子，被蜂胶素处理后在BV2细胞中基本上被诱导。也，在用达啡肽治疗的EAE小鼠中观察到HO-1的水平明显升高，同时丙二醛水平降低。更重要的是，BV2小胶质细胞中HO-1的缺失在很大程度上消除了蜂胶蛋白介导的炎症反应抑制作用。在一起，我们的数据表明，蜂胶蛋白在EAE的发病过程中具有抗炎和神经保护作用，这至少部分取决于其对HO-1的调节。