Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAPK pathway for extracellular ATP-induced apoptosis in macrophage

Takuya Noguchi; Ken Ishii; Hisashi Fukutomi; Isao Naguro; Atsushi Matsuzawa; Kohsuke Takeda; Hidenori Ichijo

doi:10.1074/jbc.M708402200

Requirement of reactive oxygen species-dependent activation of ASK1-p38 MAPK pathway for extracellular ATP-induced apoptosis in macrophage

J Biol Chem. 2008 Mar 21;283(12):7657-65. doi: 10.1074/jbc.M708402200. Epub 2008 Jan 22.

Authors

Takuya Noguchi¹, Ken Ishii, Hisashi Fukutomi, Isao Naguro, Atsushi Matsuzawa, Kohsuke Takeda, Hidenori Ichijo

Affiliation

¹ 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.

PMID: 18211888
DOI: 10.1074/jbc.M708402200

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Adenosine Triphosphate / pharmacology*
Animals
Apoptosis / drug effects*
Apoptosis / physiology
Enzyme Activation / drug effects
Enzyme Activation / physiology
Humans
MAP Kinase Kinase Kinase 5 / genetics
MAP Kinase Kinase Kinase 5 / metabolism*
MAP Kinase Signaling System / drug effects*
MAP Kinase Signaling System / physiology
Macrophages / enzymology*
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mice
Mice, Knockout
NADPH Oxidase 2
NADPH Oxidases / genetics
NADPH Oxidases / metabolism
Reactive Oxygen Species / metabolism*
Receptors, Purinergic P2 / genetics
Receptors, Purinergic P2 / metabolism
Receptors, Purinergic P2X7
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Membrane Glycoproteins
P2RX7 protein, human
P2rx7 protein, mouse
Reactive Oxygen Species
Receptors, Purinergic P2
Receptors, Purinergic P2X7
Adenosine Triphosphate
CYBB protein, human
Cybb protein, mouse
NADPH Oxidase 2
NADPH Oxidases
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 5
MAP3K5 protein, human
Map3k5 protein, mouse