雷公藤甲素诱导Th17/Treg失衡致肝毒性及肝毒易感性的分子机制研究

免疫功能紊乱是肝毒性发生的重要机制。雷公藤甲素（TP）是雷公藤的主要活性成分，但具有显著的肝毒性。我们前期研究表明TP可致肝脏中Th17/Treg失衡诱发肝脏的免疫损伤及肝毒性易感性。最近工作发现TP可致诱导Th17/Treg失衡的关键因子IL-1β及IL-6表达增高，且提示可上调调控IL-1β及IL-6表达的NF-kB信号活性。ACC-1介导的脂肪酸从头合成在Th17/Treg之间转换中发挥重要调控作用，研究发现TP可增加肝组织中调控脂质代谢关键酶LXRα及ACC-1的表达。因此，我们提出如下假设：TP通过LXRα-ACC-1信号介导肝细胞脂质代谢紊乱以及激活肝细胞中NF-kB信号促进IL-6及IL-1β的表达分泌，致Th17/Treg失衡而加重肝毒性及诱发肝毒性易感性。本研究对于全面阐释TP致肝毒性的机制具有重要的科学意义，并为预防及抗TP肝毒性治疗提供新的有效分子靶点。

Immune dysfunction is an important mechanism of hepatotoxicity. Triptolide (TP) is the main active ingredient of Tripterygium wilfordii with significant hepatotoxicity however. Our previous study has shown that TP could cause Th17/Treg imbalance which induces liver immune injury and hepatotoxical susceptibility. It has been showed that TP up-regulated the expression of IL-1β and IL-6 increasing the risk of Th17/Treg imbalance via NF-κB signaling pathway. It is known that ACC-1-mediated de novo fatty acid synthesis plays an important regulatory role in the conversion between Th17 and Treg. As a key enzyme of lipid metabolism, the expression of ACC-1 could also be increased by TP treatment. Therefore, we supposed that TP-induced Th17/Treg imbalance is resulted from IL-6 and IL-1β expression increase through LXRα/ACC-1-mediated lipid metabolism disorders and NF-κB pathway activation which induces hepatotoxicity and hepatotoxical susceptibility. This study has great scientific significance for explaining the mechanism of TP-induced hepatotoxicity and provides new effective targets for prevention and treatment.