ROS-JNK1/2-dependent activation of autophagy is required for the induction of anti-inflammatory effect of dihydroartemisinin in liver fibrosis
ROS-JNK1/2-dependent activation of autophagy is required for the induction of anti-inflammatory effect of dihydroartemisinin in liver fibrosis
复制标题
双氢青蒿素在肝纤维化中的抗炎作用需要ROS-JNK1/2依赖性激活自噬
DOI：
10.1016/j.freeradbiomed.2016.10.498
复制
发表时间：
2016
影响因子：
7.4
通讯作者：
Zheng S
中科院分区：
文献类型：
--
作者：
Zhang Z;Guo M;Zhao S;Shao J;Zheng S
越来越多的证据表明，自噬是一种与炎症相关的防御机制，可以抵御包括肝纤维化在内的疾病。因此，自噬可能是治疗肝纤维化药物开发的一个新的药理靶点。在本研究中，我们试图研究双氢青蒿素(DHA)对自噬的影响，并进一步探讨DHA抗炎作用的分子机制。我们发现DHA似乎在控制过度炎症方面起着至关重要的作用。DHA可抑制大鼠肝纤维化模型的炎症反应，并抑制活化的肝星状细胞(HSCs)中促炎症细胞因子的表达。有趣的是，DHA增加了激活的HSC的自噬小体生成和自噬通量，这是DHA抗炎作用的根本机制。自噬耗竭减弱了DHA的抗炎作用，而自噬诱导与DHA有协同作用。重要的是，我们的研究还确定了活性氧物种(ROS)在促进DHA诱导的自噬中的关键作用。抗氧化剂，如谷胱甘肽和N-乙酰半胱氨酸，显著抑制ROS的产生，进而阻止DHA诱导的自噬小体的产生和自噬通量。此外，我们还发现c-Jun氨基末端激酶1/2(JNK1/2)是ROS下游的信号分子，介导DHA诱导自噬。使用选择性JNK1/2抑制剂(SP600125)或siJNK1/2下调JNK1/2活性，可抑制DHA诱导的自噬。总之，这些结果为揭示DHA诱导抗炎作用的分子机制提供了新的启示，从而表明了使用DHA类自噬前体药物治疗炎症性疾病的可能性。
Accumulating evidence identifies autophagy as an inflammation-related defensive mechanism against diseases including liver fibrosis. Therefore, autophagy may represent a new pharmacologic target for drug development to treat liver fibrosis. In this study, we sought to investigate the effect of dihydroartemisinin (DHA) on autophagy, and to further examine the molecular mechanisms of DHA-induced anti-inflammatory effects. We found that DHA appeared to play an essential role in controlling excessive inflammation. DHA suppressed inflammation in rat liver fibrosis model and inhibited the expression of proinflammatory cytokines in activated hepatic stellate cells (HSCs). Interestingly, DHA increased the autophagosome generation and autophagic flux in activated HSCs, which is underlying mechanism for the anti-inflammatory activity of DHA. Autophagy depletion impaired the induction of anti-inflammatory effect of DHA, while autophagy induction showed a synergistic effect with DHA. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of DHA-induced autophagy. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented DHA-induced autophagosome generation and autophagic flux. Besides, we found that c-Jun N-terminal kinase1/2 (JNK1/2) was a downstream signaling molecule of ROS that mediated the induction of autophagy by DHA. Down-regulation of JNK1/2 activity, using selective JNK1/2 inhibitor (SP600125) or siJNK1/2, led to an inhibition of DHA-induced autophagy. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced anti-inflammatory effects, by which points to the possibility of using DHA based proautophagic drugs for the treatment of inflammatory diseases.