自核酸的TLR识别阻碍了狼中的葡萄糖皮质体活性
Cristiana Guiducci1, Mei Gong, Zhaohui Xu
1Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA.
Nature
|June 19, 2010
概括
葡萄糖皮质类药物在治疗狼 (SLE) 中效率较低,因为在等离子细胞树突细胞 (PDC) 上的收费类受体 (TLR7/9) 阻止了它们的抗炎作用. 抑制TLR7/9可能提供一种新的治疗策略.
科学领域:
- 免疫学 免疫学 免疫学
- 类风湿病学 类风湿病学
- 分子生物学分子生物学
背景情况:
- 葡萄糖皮质类药物是对自身免疫性疾病的标准治疗方法,如全身性红斑狼 (SLE).
- 目前的治疗方法往往无法在大多数SLE患者中保持疾病控制,因此需要积极的治疗方法.
- 葡萄糖皮质醇的抗炎作用主要归因于NF-kappaB的抑制.
研究的目的:
- 为了研究为什么葡萄糖皮质类药物在治疗SLE患者中效果较差.
- 探索7号和9号收费类受体 (TLRs) 在SLE病变和葡萄糖皮质体耐药性中的作用.
- 为了确定SLE治疗的潜在新治疗点.
主要方法:
- 使用SLE患者和易患狼的小鼠模型的体外和体内研究.
- 通过TLR7和TLR9.9刺激血细胞树突细胞 (PDCs).
- 对NF-kappaB通路激活和葡萄糖皮质体对PDCs的影响的分析.
- 对干扰素 (IFN) 水平的测量.
主要成果:
- 在PDC中TLR7和TLR9的刺激激活了NF-kappaB通路,这对它们的生存至关重要.
- 葡萄糖皮质类药物不会抑制PDCs中的NF-kappaB激活.
- 这种缺乏抑制可以防止葡萄糖皮质醇诱导的PDC死亡,并降低全身IFN-α水平,解释了SLE中的葡萄糖皮质醇耐药性.
- 这些发现在SLE患者和易患狼的小鼠中一致.
结论:
- 通过TLR7/9激活等离子体树突细胞,有助于SLE的葡萄糖皮质体耐药性.
- 通过TLRs识别自身核酸在SLE病变和治疗不响应方面发挥着关键作用.
- 针对TLR7和TLR9信号的抑制剂代表了开发SLE新型皮质类固醇节约疗法的有希望的战略.
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