Aromatic-turmerone's anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling
Aromatic-turmerone's anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling
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DOI：
10.1016/j.neuint.2012.06.020
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发表时间：
2012-10-01
影响因子：
4.2
通讯作者：
Lee, Sang-Joon
中科院分区：
文献类型：
--
作者：
Park, Sun Young;Kim, Young Hun;Lee, Sang-Joon
尽管有数据支持阿姜黄酮在体外具有免疫调节作用，但其潜在的信号传导途径在很大程度上尚不清楚。在这里，我们研究了阿姜黄酮在 LPS 刺激的 BV-2 小胶质细胞中的抗神经炎症特性。促炎细胞因子和趋化因子 PGE(2) 增加。 ar-姜黄酮抑制 LPS 刺激的小胶质细胞中 NO 和 ROS 的产生以及 MMP-9 酶活性。随后的机制研究表明，ar-姜黄酮抑制 LPS 诱导的 JNK、p38 MAPK 和 NF-κ B 激活。此外，ar-姜黄酮降低了 LPS 诱导的 STAT-1 的磷酸化。此外，ar-姜黄酮还能增加抗炎转录因子 STAT-3 的磷酸化。接下来我们证明，ar-姜黄酮诱导的 HO-1 和 Nrf-2 激活抑制了 LPS 诱导的小胶质细胞中神经炎症分子的激活，并且 HO-1 信号的下调足以诱导小胶质细胞中 iNOS、COX-2 的表达和 ROS 的产生。有趣的是，我们发现芳姜黄酮通过上调小胶质细胞中的 cAMP 水平来诱导 CREB 磷酸化。此外，通过 PICA 介导的 CREB 磷酸化激活 HO-1 减弱了 LPS 诱导的小胶质细胞中神经炎症分子的表达。总体而言，本研究结果表明 HO-1 及其上游效应子 PKA 在 LPS 刺激的小胶质细胞中 ar-姜黄酮的抗神经炎症反应中发挥着关键作用。 (C) 2012 Elsevier Ltd. 保留所有权利。
Despite data supporting an immune-modulating effect of ar-turmerone in vitro, the underlying signaling pathways are largely unknown. Here, we investigated the anti-neuroinflammatory properties of ar-turmerone in LPS-stimulated BV-2 microglial cells. Increased pro-inflammatory cytokines and chemokines, PGE(2). NO and ROS production and MMP-9 enzymatic activity in LPS-stimulated microglial cells was inhibited by ar-turmerone. Subsequent mechanistic studies revealed that ar-turmerone inhibited LPS-induced JNK, p38 MAPK and NF-kappa B activation. Furthermore, ar-turmerone decreased the phosphorylation of LPS-induced STAT-1. Additionally, ar-turmerone increased the phosphorylation of STAT-3, an anti-inflammatory transcription factor. We next demonstrated that ar-turmerone induced HO-1 and Nrf-2 activation suppressed the activation of neuroinflammatory molecules in LPS-induced microglial cells, and that down-regulation of HO-1 signals was sufficient to induce the expression of iNOS, COX-2 and ROS production in microglial cells. Interestingly, we found that ar-turmerone induced phosphorylation of CREB by upregulating the cAMP level in microglial cells. Furthermore, HO-1 activation via PICA-mediated CREB phosphorylation attenuated the expression of neuroinflammatory molecules in LPS-induced microglial cells. Overall, the results of this study demonstrate that HO-1 and its upstream effectors PKA play a pivotal role in the anti-neuroinflammatory response of ar-turmerone in LPS-stimulated microglia. (C) 2012 Elsevier Ltd. All rights reserved.