Role of endogenous ATP in the regulation of pro- and anti antiinflammatorymediator production

Es. Vizi et al., Role of endogenous ATP in the regulation of pro- and anti antiinflammatorymediator production, DRUG DEV R, 53(2-3), 2001, pp. 117-125
Citations number
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ISSN journal
0272-4391 → ACNP
Year of publication
117 - 125
SICI code
While a wealth of data is accumulating on the immunomodulatory role of puri ne nucleotides and nucleosides, a major challenge has become to understand the factors that govern purine availability and its dynamics at the site of inflammation. it has been shown that ATP is co-stored with classical trans mitters (noradrenaline, acetylcholine, glutamate) in nerve terminals. Furth ermore, ATP is co-released with the classical transmitters in response to c hemical and electrical depolarization. Our recent studies showed that ATP c ould also be released from postsynaptic cells in response to the action of primary transmitters (noradrenaline, acetylcholine, ATP) on their receptors (cascade transmission) (Vizi et al. [1992] Neuroscience 50:455-465; Vizi a nd Sperlagh [1999] Prog Brain Res 120:159-169). Apart from direct leakage d ue to cell injury, ATP and its metabolic degradation products, ADP, AMP, an d adenosine accumulate extracellularly during episodes of metabolic stress caused by ischemia and inflammation. In addition, we have recently shown (S perlagh et al. [1998] Neurochem Int 33:209-215) that bacterial lipopolysacc haride (LPS) is also a powerful stimulus to elicit endogenous ATP release i n cultured RAW264.7 macrophages. The P2Z/P2(X7) receptor agonist 3'-O-(4-be nzoylbenzoyl)-adenosine 5'-triphosphate (BzATP, 10-250 muM) and ATP (30-300 muM) increased, in a concentration-dependent manner, LPS (10 mug/ml)-induc ed nitric oxide production in the RAW 264.7 cells. On the other hand, pretr eatment with oxidized adenosine triphosphate (oxyATP), a selective P2Z/P2(X 7) receptor antagonist (300 muM to 1 mM), strongly decreased LPS-induced ni tric oxide production. Furthermore, in macrophages pretreated with oxyATP ( 300 muM to 1 mM), BzATP and ATP did not affect LPS-induced nitric oxide pro duction. Finally, our recent data show that ATP and its analogs suppress th e production of both TNF-alpha and IL-12 by I-PS-stimulated mouse peritonea l macrophages (Hasko et al. [2000] Br J Pharmacol 129:909-914). Because the effect of ATP was prevented by treatment with adenosine deaminase, it can be suggested that the suppressive effect of ATP on cytokine production was due to its degradation products. Taken together, our findings support the v iew that endogenous ATP released from various sources plays an important ro le in the regulation of macrophage responsiveness during inflammation. (C) 2001 Wiley-Liss, Inc.