title: Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAPK pathway for extracellular ATP-induced apoptosis in macrophage.
abstract: Extracellular ATP, an autocrine or paracrine intercellular transmitter, is known to induce apoptosis in macrophages. However, the precise signaling mechanisms of ATP-induced apoptosis remain to be elucidated. Here we showed that activation of p38 mitogen-activated protein kinase (MAPK) plays a critical role in ATP-induced apoptosis. p38 activation and apoptosis in macrophages were induced by ATP. ATP-induced apoptosis was mediated in part by production of reactive oxygen species (ROS) derived from NOX2/gp91(phox), a component of the NADPH oxidase complex expressed in macrophages and neutrophils. Furthermore, ATP-induced ROS generation, p38 activation, and apoptosis were almost completely inhibited by selective P2X(7) receptor antagonists. We also found that ATP-induced apoptosis were diminished in ASK1-deficient macrophages accompanied by the lack of p38 activation. These results demonstrate that ROS-mediated activation of the ASK1-p38 MAPK pathway downstream of P2X(7) receptor is required for ATP-induced apoptosis in macrophages.
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Center of Excellence Program, Japan Science and Technology Corporation, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Noguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Ishii
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fukutomi
authors.forename: Isao
authors.initials: I
authors.lastname: Naguro
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008264:Macrophages / Q000201:enzymology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D017382:Reactive Oxygen Species; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse