Production and Release of Neuroprotective Tumor Necrosis Factor by P2X7Receptor-Activated Microglia
Open accessAbstract
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 P2X 7 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 P2X 7 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 P2X 7 agonist 2′-3′-O-(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF-α 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 P2X 7 receptor to activate JNK and p38. Finally, our data suggest that P2X 7 receptor-activated microglia protect neurons against glutamate toxicity primarily because they are able to release TNF.
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P2X7 receptor activation also promotes the release of other inflammatory mediators such as IL-6, TNF-α, CCL2, CCL3, and CXCL2.
“Moreover, P2X7 receptor activation also promotes the release of other inflammatory mediators such as IL-6, TNF-α, CCL2, CCL3, and CXCL2 [77–80].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [78]
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- Authors
- Suzuki, T., Hide, I., Ido, K., Kohsaka, S., Inoue, K., & Nakata, Y.
- Affiliations
- Hiroshima University (JP)
- National Center of Neurology and Psychiatry (JP)
- Kyushu University (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-01-07
- Volume
- 24
- Issue
- 1
- Pages
- 1-7
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729576
- OpenAlex
- W2023830878
- Cited by
- 394
- References
- 41
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 8 · 2021: 10 · 2020: 21 · 2019: 6 · 2018: 16 · 2017: 11 · 2016: 17 · 2015: 21 · 2014: 14 · 2013: 27 · 2012: 20
- FWCI
- 17.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (11670089, 15590229)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- TNF-α, microglia, ATP, neuroprotection, JNK, p38 MAPK, ERK, MEK, TNF mRNA expression, nuclear transport, tyrosine kinase, Src family kinases, glutamate-induced neuronal death, neuroinflammation, brilliant blue
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Nucleus, Cell Survival, Cells, Cultured, Neurons, Protein-Tyrosine Kinases, RNA, Messenger, Tumor Necrosis Factor-alpha, Cell Death, Microglia, Receptors, Purinergic P2, Neuroprotective Agents, Glutamic Acid, Mitogen-Activated Protein Kinases, Active Transport, Cell Nucleus, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Rats, Receptors, Purinergic P2X7
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