title: Aromatic-turmerone's anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling.
abstract: 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.
authors: Bio-IT Fusion Technology Research Institute, Pusan National University, Busan 609-735, Republic of Korea.
authors: Sun Young
authors: SY
authors: Park
authors: Young Hun
authors: YH
authors: Kim
authors: YoungHee
authors: Y
authors: Kim
authors: Sang-Joon
authors: SJ
authors: Lee
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000502:physiology*; D007659:Ketones / Q000494:pharmacology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D010936:Plant Extracts / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007659:Ketones; D008565:Membrane Proteins; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C078098:ar-turmerone; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases