RRC ID 63574
著者 Hirata Y, Nada Y, Yamada Y, Toyama T, Fukunaga K, Hwang GW, Noguchi T, Matsuzawa A.
タイトル Elaidic Acid Potentiates Extracellular ATP-Induced Apoptosis via the P2X7-ROS-ASK1-p38 Axis in Microglial Cell Lines.
ジャーナル Biol Pharm Bull
Abstract trans-Fatty acids (TFAs) are unsaturated fatty acids with at least one carbon-carbon double bond in trans configuration. TFA consumption has been epidemiologically associated with neurodegenerative diseases (NDs) including Alzheimer's disease. However, the underlying mechanisms of TFA-related NDs remain unknown. Here, we show a novel microglial signaling pathway that induces inflammation and cell death, which is dramatically enhanced by elaidic acid (EA), the most abundant TFA derived from food. We found that extracellular ATP, one of the damage-associated molecular patterns (DAMPs) leaked from injured cells, induced activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway, which is one of the major stress-responsive mitogen-activated protein (MAP) kinase signaling pathways, and subsequent caspase-3 cleavage and DNA ladder formation (hallmarks of apoptosis) in mouse microglial cell lines including BV2 and MG6 cells. Furthermore, we found that in these microglial cell lines, EA, but not its cis isomer oleic acid, facilitated extracellular ATP-induced ASK1/p38 activation and apoptosis, which was suppressed by pharmacological inhibition of either p38, reactive oxygen species (ROS) generation, P2X purinoceptor 7 (P2X7), or Ca2+/calmodulin-dependent kinase II (CaMKII). These results demonstrate that in microglial cells, extracellular ATP induces activation of the ASK1-p38 MAP kinase pathway and ultimately apoptosis downstream of P2X7 receptor and ROS generation, and that EA promotes ATP-induced apoptosis through CaMKII-dependent hyperactivation of the ASK1-p38 pathway, in the same manner as in macrophages. Our study may provide an insight into the pathogenesis of NDs associated with TFAs.
巻・号 43(10)
ページ 1562-1569
公開日 2020-1-1
DOI 10.1248/bpb.b20-00409
PMID 32999166
MeSH Adenosine Triphosphate / administration & dosage* Animals Apoptosis / drug effects Apoptosis / physiology Cell Line Dose-Response Relationship, Drug Drug Synergism Extracellular Fluid / drug effects Extracellular Fluid / metabolism MAP Kinase Kinase Kinase 5 / metabolism* MAP Kinase Signaling System / drug effects* MAP Kinase Signaling System / physiology Mice Microglia / drug effects* Microglia / metabolism Oleic Acids / administration & dosage* Reactive Oxygen Species / metabolism* Receptors, Purinergic P2X7 / metabolism*
IF 1.863
リソース情報
ヒト・動物細胞 MG-63(RCB1890)