β-Lapachone is a naturally occurring quinine, originally isolated from the bark of the lapacho tree (Tabebuia avellanedae) which is currently being evaluated in clinical trials for the treatment of cancer. In addition, recent investigations suggest its potential application for treatment of inflammatory diseases. Multiple sclerosis (MS) is an autoimmune disorder characterized by CNS inflammation and demyelination. Reactive T cells including IL-17 and IFN-γ-secreting T cells are believed to initiate MS and the associated animal model system experimental autoimmune encephalomyelitis (EAE). IL-12 family cytokines secreted by peripheral dendritic cells (DCs) and CNS microglia are capable of modulating T-cell phenotypes. The present studies demonstrated that β-lapachone selectively inhibited the expression of IL-12 family cytokines including IL-12 and IL-23 by DCs and microglia, and reduced IL-17 production by CD4(+) T-cells indirectly through suppressing IL-23 expression by microglia. Importantly, our studies also demonstrated that β-lapachone ameliorated the development on EAE. β-Lapachone suppression of EAE was associated with decreased expression of mRNAs encoding IL-12 family cytokines, IL-23R and IL-17RA, and molecules important in Toll-like receptor signaling. Collectively, these studies suggest mechanisms by which β-lapachone suppresses EAE and suggest that β-lapachone may be effective in the treatment of inflammatory diseases such as MS.

译文

β-Lapachone是一种天然存在的奎宁,最初是从lapacho树 (Tabebuia avellanedae) 的树皮中分离出来的,目前正在治疗癌症的临床试验中进行评估。此外,最近的研究表明其在治疗炎症性疾病中的潜在应用。多发性硬化症 (MS) 是一种以中枢神经系统炎症和脱髓鞘为特征的自身免疫性疾病。包括IL-17和IFN-γ 分泌T细胞的反应性T细胞被认为会引发MS和相关的动物模型系统实验性自身免疫性脑脊髓炎 (EAE)。外周树突状细胞 (dc) 和CNS小胶质细胞分泌的IL-12家族细胞因子能够调节T细胞表型。本研究表明,β-lapachone选择性地抑制dc和小胶质细胞IL-12和IL-23等IL-12家族细胞因子的表达,并通过抑制小胶质细胞的IL-23表达间接降低CD4 () T细胞的IL-17产生。重要的是,我们的研究还表明 β-lapachone改善了EAE的发育。EAE的 β-Lapachone抑制与编码IL-12家族细胞因子,IL-23R和IL-17RA以及Toll样受体信号重要分子的mrna表达降低有关。总的来说,这些研究表明 β-拉帕酮抑制EAE的机制,并表明 β-拉帕酮可能有效治疗MS等炎症性疾病。

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