Aromatic-turmerone's anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling

被引:33
作者
Park, Sun Young [2 ,3 ]
Kim, Young Hun [2 ]
Kim, YoungHee [3 ]
Lee, Sang-Joon [1 ]
机构
[1] Pusan Natl Univ, Dept Microbiol, Pusan 609735, South Korea
[2] Pusan Natl Univ, BioIT Fus Technol Res Inst, Pusan 609735, South Korea
[3] Pusan Natl Univ, Dept Mol Biol, Pusan 609735, South Korea
关键词
ar-Turmerone; Neuroinflammation; MMP-9; ROS; HO-1; PKA; CENTRAL-NERVOUS-SYSTEM; KAPPA-B; THERAPEUTIC TARGET; BRAIN INFLAMMATION; OXIDATIVE STRESS; GENE-EXPRESSION; BINDING PROTEIN; NITRIC-OXIDE; ACTIVATION; PATHWAYS;
D O I
10.1016/j.neuint.2012.06.020
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:767 / 777
页数:11
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