Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-κB/IκBα transcriptional complex
Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-κB/IκBα transcriptional complex
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DOI：
10.1016/j.jneuroim.2009.08.017
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发表时间：
2009-12-10
影响因子：
3.3
通讯作者：
Raskin, Ilya
中科院分区：
文献类型：
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作者：
Kizelsztein, Pablo;Komarnytsky, Slavko;Raskin, Ilya
现有的多发性硬化症（MS）治疗需要频繁注射，并有显着的副作用。在这项研究中，我们检测了口服雷公藤甲素的免疫调节特性，雷公藤甲素是一种主要的二萜类三环氧化物，从缠绕的雷公藤藤中分离出来。用PLP（139-151）肽致敏SJL/J小鼠，并从EAE诱导当天（预防方案）和临床体征发作后（治疗方案）用雷公藤内酯醇（100 μ g/kg/天）口服治疗。雷公藤内酯醇延迟疾病发作，减少临床症状，降低复发率，并抑制炎症和脱髓鞘的中枢神经系统组织的EAE小鼠相比，溶剂治疗的动物。分子生物学分析显示，雷公藤甲素治疗动物的CNS组织中的热休克蛋白70（Hsp 70）mRNA和蛋白质的显着增加。来自EAE组织和体外巨噬细胞的细胞因子和趋化因子表达分析检测到关键促炎mRNA的减少。雷公藤内酯醇通过稳定NF-κ B/I-κ B α复合物抑制I-κ B α磷酸化和NF-κ B核转位，这可能是由于NF-κ B和Hsp 70蛋白之间的直接物理相互作用。淋巴结细胞增殖试验证实了雷公藤甲素的免疫抑制作用。我们的数据表明，每天口服雷公藤内酯醇不仅具有预防作用，而且对EAE有治疗作用。这些作用可能是由于雷公藤内酯醇引起的Hsp 70水平增加和NF-κ B/I κ B α复合物的稳定导致炎症反应减弱。(C)2009爱思唯尔有限公司版权所有。
Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. in this study, we examined the immunomodulatory properties of orally administered triptolide, a major diterpenoid triepoxide isolated from a twining vine Tripterygium wilfordii. SJL/J mice were primed with PLP(139-151) peptide and orally treated with triptolide (100 mu g/kg per day) from the day of EAE induction (preventive regime) and after the onset of clinical signs (therapeutic regime). Triptolide delayed disease onset, reduced clinical symptoms, decreased the relapse rate, and suppressed inflammation and demyelination in CNS tissue of EAE mice when compared to vehicle-treated animals. Molecular analysis revealed a marked increase of heat shock protein 70 (Hsp70) mRNA and protein in the CNS tissue of triptolide-treated animals. Cytokine and chemokine expression analysis from EAE tissues and in vitro macrophages detected a decrease of key pro-inflammatory mRNAs. Triptolide inhibited I kappa B alpha phosphorylation and NF-kappa B nuclear translocation by stabilization of NF-kappa B/I kappa B alpha complex, possibly due to a direct physical interaction between NF-kappa B and Hsp70 proteins. Lymph node cell proliferation assay in EAE confirmed the immunosuppressive efficacy of triptolide. Our data indicate that daily oral administration of triptolide exhibits not only a preventive but also a therapeutic effect on EAE. These effects might be explained by the increase in Hsp70 levels driven by triptolide and stabilization of the NF-kappa B/I kappa B alpha complex leading to an attenuated inflammatory response. (C) 2009 Elsevier B.V. All rights reserved.