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

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-κB 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 PKA-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.