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Bi‐functional effects of ATP/P2 receptor activation on tumor necrosis factor‐alpha release in lipopolysaccharide‐stimulated astrocytes
Author(s) -
Kucher Brandon M.,
Neary Joseph T.
Publication year - 2005
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 - 10.1111/j.1471-4159.2004.02885.x
Subject(s) - tumor necrosis factor alpha , purinergic receptor , agonist , receptor , astrocyte , lipopolysaccharide , purinergic signalling , adenosine , p2 receptor , chemistry , p2y receptor , proinflammatory cytokine , extracellular , cytokine , endocrinology , neuroinflammation , medicine , pharmacology , biology , adenosine receptor , inflammation , biochemistry , central nervous system
Neuroinflammation is associated with a variety of CNS pathologies. Levels of tumor necrosis factor‐alpha (TNF‐α), a major proinflammatory cytokine, as well as extracellular ATP, are increased following various CNS insults. Here we report on the relationship between ATP/P2 purinergic receptor activation and lipopolysaccharide (LPS)‐induced TNF‐α release from primary cultures of rat cortical astrocytes. Using ELISA, we confirmed that treatment with LPS stimulated the release of TNF‐α in a concentration and time dependent manner. ATP treatment alone had no effect on TNF‐α release. LPS‐induced TNF‐α release was attenuated by 1 m m ATP, a concentration known to activate P2X7 receptors. Consistent with this, 3′‐ O ‐(4‐Benzoyl)benzoyl‐ATP (BzATP), a P2X7 receptor agonist, also attenuated LPS‐induced TNF‐α release. This reduction in TNF‐α release was not due to loss of cell viability. Adenosine and 2‐chloroadenosine were ineffective, suggesting that attenuation of LPS‐induced TNF‐α release by ATP was not due to ATP breakdown and subsequent activation of adenosine/P1 receptors. Interestingly, treatment of astrocyte cultures with 10 µ m or 100 µ m ATP potentiated TNF‐α release induced by a submaximal concentration of LPS. UTP and 2methylthioADP (2‐MeSADP), P2Y receptor agonists, also enhanced this LPS‐induced TNF‐α release. Our observations demonstrate opposing effects of ATP/P2 receptor activation on TNF‐α release, i.e. P2X receptor activation attenuates, whereas P2Y receptor activation potentiates TNF‐α release in LPS‐stimulated astrocytes. These observations suggest a mechanism whereby astrocytes can sense the severity of damage in the CNS via ATP release from damaged cells and can modulate the TNF‐α mediated inflammatory response depending on the extracellular ATP concentration and corresponding type of astrocyte ATP/P2 receptor activated.