Triptolide induces anti-inflammatory cellular responses.
Triptolide induces anti-inflammatory cellular responses.
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DOI：
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发表时间：
2009-03
影响因子：
2.2
通讯作者：
Ranyia Matta;Xianxi Wang;H. Ge;W. Ray;L. Nelin;Yusen Liu
中科院分区：
文献类型：
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作者：
Ranyia Matta;Xianxi Wang;H. Ge;W. Ray;L. Nelin;Yusen Liu
几个世纪以来，雷公藤在中医中一直被用来治疗类风湿性关节炎，这是一种与促炎细胞因子-肿瘤坏死因子-α的产生增加相关的自身免疫性疾病。雷公藤甲素是一种从雷公藤中提纯的化合物，具有较强的抗炎和免疫抑制活性。在这项研究中，我们研究了雷公藤甲素对内毒素(LPS)处理的巨噬细胞整体基因表达谱的影响。我们发现，内毒素刺激导致117个基因的表达增加5倍，而雷公藤甲素使其中47个基因的表达受到50%的抑制。在被内毒素强烈诱导并被雷公藤甲素显著抑制的基因中，有很大一部分是促炎细胞因子和趋化因子基因，包括肿瘤坏死因子-α、白介素1-β和白介素6。有趣的是，内毒素还诱导了微小RNA-155(miR-155)前体BIC的表达，而雷公藤甲素对其有抑制作用。证实了基因芯片的结果，我们发现雷公藤甲素以剂量依赖的方式阻断了这些促炎细胞因子和miR-155的诱导。在低至10-50 nM的浓度下，可以观察到促炎症细胞因子的表达被显著抑制。但雷公藤内酯醇不能抑制脂多糖刺激后IkappaBalpha的磷酸化或降解，也不影响核因子-kappaB的DNA结合活性。令人惊讶的是，我们发现雷公藤甲素不仅抑制了核因子-kappaB调控的报告转录，而且还显著地阻断了其他转录因子的活性。我们的研究为雷公藤的治疗机制提供了一个可信的解释。
Tripterygium wilfordii Hook F. has been used for centuries in traditional Chinese medicine to treat rheumatoid arthritis, an autoimmune disease associated with increased production of the pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha. Triptolide is a compound originally purified from T. wilfordii Hook F. and has potent anti-inflammatory and immunosuppressant activities. In this study, we investigated the effect of triptolide on the global gene expression patterns of macrophages treated with lipopolysaccharide (LPS). We found that LPS stimulation resulted in >5-fold increase in expression of 117 genes, and triptolide caused a >50% inhibition in 47 of the LPS-inducible 117 genes. A large portion of the genes that were strongly induced by LPS and significantly inhibited by triptolide were pro-inflammatory cytokine and chemokine genes, including TNF-alpha, IL-1beta, and IL-6. Interestingly, LPS also induced the expression of micro-RNA-155 (miR-155) precursor, BIC, which was inhibited by triptolide. Confirming the cDNA array results, we demonstrated that triptolide blocked the induction of these pro-inflammatory cytokines as well as miR-155 in a dose-dependent manner. Profound inhibition of pro-inflammatory cytokine expression was observed at concentrations as low as 10-50 nM. However, triptolide neither inhibited the phosphorylation or degradation of IkappaBalpha after LPS stimulation, nor affected the DNA-binding activity of NF-kappaB. Surprisingly, we found that triptolide not only inhibited NF-kappaB-regulated reporter transcription, but also dramatically blocked the activity of other transcription factors. Our study offers a plausible explanation of the therapeutic mechanism of T. wilfordii Hook F.