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Extracellular ATP Triggers Tumor Necrosis Factor‐α Release from Rat Microglia
Author(s) -
Hide Izumi,
Tanaka Masaya,
Inoue Atsuko,
Nakajima Kazuyuki,
Kohsaka Shinichi,
Inoue Kazuhide,
Nakata Yoshihiro
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0750965.x
Subject(s) - microglia , extracellular , tumor necrosis factor alpha , mapk/erk pathway , microbiology and biotechnology , kinase , protein kinase a , p38 mitogen activated protein kinases , agonist , receptor , neuroglia , biology , chemistry , endocrinology , biochemistry , inflammation , immunology , central nervous system
Brain microglia are a major source of inflammatory cytokines, such as tumor necrosis factor‐α (TNF‐α), which have been implicated in the progression of neurodegenerative diseases. Recently, microglia were revealed to be highly responsive to ATP, which is released from nerve terminals, activated immune cells, or damaged cells. It is not clear, however, whether released ATP can regulate TNF‐α secretion from microglia. Here we demonstrate that ATP potently stimulates TNF‐α release, resulting from TNF‐α mRNA expression in rat cultured brain microglia. The TNF‐α release was maximally elicited by 1 m M ATP and also induced by a P2X 7 receptor‐selective agonist, 2′‐ and 3′‐ O ‐(4‐benzoylbenzoyl)adenosine 5′‐triphosphate, suggesting the involvement of P2X 7 receptor. ATP‐induced TNF‐α release was Ca 2+ ‐dependent, and a sustained Ca 2+ influx correlated with the TNF‐α release in ATP‐stimulated microglia. ATP‐induced TNF‐α release was inhibited by PD 098059, an inhibitor of extracellular signal‐regulated protein kinase (ERK) kinase 1 (MEK1), which activates ERK, and also by SB 203580, an inhibitor of p38 mitogen‐activated protein kinase. ATP rapidly activated both ERK and p38 even in the absence of extracellular Ca 2+ . These results indicate that extracellular ATP triggers TNF‐α release in rat microglia via a P2 receptor, likely to be the P2X 7 subtype, by a mechanism that is dependent on both the sustained Ca 2+ influx and ERK/p38 cascade, regulated independently of Ca 2+ influx.