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The Journal of Neuroscience, January 7, 2004, 24(1):1-7; doi:10.1523/JNEUROSCI.3792-03.2004

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Cellular/Molecular
Production and Release of Neuroprotective Tumor Necrosis Factor by P2X₇ Receptor-Activated Microglia

Tomohisa Suzuki,¹ Izumi Hide,¹ Katsutoshi Ido,¹ Shinichi Kohsaka,² Kazuhide Inoue,^3,4 and Yoshihiro Nakata¹

¹Department of Pharmacology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan, ²Department of Neurochemistry, National Institute of Neuroscience, Tokyo 187-8502, Japan, ³Division of Biosignaling, National Institute of Health Science, Tokyo 158-8501, Japan, and ⁴Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan

After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor (TNF). The release of TNF appears to be dependent on the P2X₇ receptor. The inhibitors 1,4-diamino-2,3-dicyano-1,4-bis[2-amino-phenylthio]butadiene (U0126), anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)IH-imidazole (SB203580), which target MEK (mitogen-activated protein kinase kinase), JNK (c-Jun N-terminal kinase), and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X₇ receptor blocker, and by genistein and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-D]pyrimidine, which are general and src-family-specific tyrosine kinase inhibitors, respectively. Most important, we found that treatment of the microglia in neuron-microglia cocultures with the P2X₇ agonist 2'-3'-O-(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF- converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Together, these findings indicate that both ERK and JNK are involved in the regulation of TNF mRNA expression, that p38 is involved in the nucleocytoplasmic transport of TNF mRNA, and that a PTK (protein tyrosine kinase), possibly a member of the src family, acts downstream of the P2X₇ receptor to activate JNK and p38. Finally, our data suggest that P2X₇ receptor-activated microglia protect neurons against glutamate toxicity primarily because they are able to release TNF.

Key words: P2X₇ receptor; TNF; MAP kinase; ATP; microglia; neuroprotection

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Received Aug 14, 2003; revised October 6, 2003; accepted October 7, 2003.

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