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

:-Lapachone是一种天然存在的奎宁,最初从lapacho树(Tabebuia avellanedae)的树皮中分离出来,目前正在临床试验中评估其治疗癌症的能力。另外,最近的研究表明其在治疗炎性疾病中的潜在应用。多发性硬化症(MS)是一种以CNS炎症和脱髓鞘为特征的自身免疫性疾病。据信包括IL-17和分泌IFN-γ的T细胞在内的反应性T细胞可引发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)和中枢神经系统小胶质细胞分泌的IL-12家族细胞因子能够调节T细胞表型。本研究表明,β-拉帕酮可选择性抑制DC和小胶质细胞的IL-12家族细胞因子(包括IL-12和IL-23)的表达,并通过抑制IL-23间接降低CD4()T细胞的IL-17产生。小胶质细胞表达。重要的是,我们的研究还表明,β-拉帕酮可改善EAE的发展。 β-拉帕酮对EAE的抑制作用与编码IL-12家族细胞因子,IL-23R和IL-17RA以及在Toll样受体信号转导中重要的分子的mRNA表达降低有关。这些研究共同提出了β-拉帕酮抑制EAE的机制,并提出了β-拉帕酮可能有效治疗诸如MS的炎性疾病。

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