Role of endogenous ATP in the regulation of pro- and antiinflammatory mediator production

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While a wealth of data is accumulating on the immunomodulatory role of purine 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 transmitters (noradrenaline, acetylcholine, glutamate) in nerve terminals. Furthermore, ATP is co-released with the classical transmitters in response to chemical and electrical depolarization. Our recent studies showed that ATP could 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 and Sperlágh [1999] Prog Brain Res 120:159-169). Apart from direct leakage due to cell injury, ATP and its metabolic degradation products, ADP, AMP, and adenosine accumulate extracellularly during episodes of metabolic stress caused by ischemia and inflammation. In addition, we have recently shown (Sperlágh et al. [1998] Neurochem Int 33:209-215) that bacterial lipopolysaccharide (LPS) is also a powerful stimulus to elicit endogenous ATP release in cultured RAW264.7 macrophages. The P2Z/P2X7 receptor agonist 3′-O-(4-benzoylbenzoyl)-adenosine 5′-triphosphate (BzATP, 10-250 μM) and ATP (30-300 μM) increased, in a concentration-dependent manner, LPS (10 μg/ml)-induced nitric oxide production in the RAW 264.7 cells. On the other hand, pretreatment with oxidized adenosine triphosphate (oxyATP), a selective P2Z/P2X7 receptor antagonist (300 μM to 1 mM), strongly decreased LPS-induced nitric oxide production. Furthermore, in macrophages pretreated with oxyATP (300 μM to 1 mM), BzATP and ATP did not affect LPS-induced nitric oxide production. Finally, our recent data show that ATP and its analogs suppress the production of both TNF-α and IL-12 by LPS-stimulated mouse peritoneal macrophages (Haskó 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 view that endogenous ATP released from various sources plays an important role in the regulation of macrophage responsiveness during inflammation.

Original languageEnglish
Pages (from-to)117-125
Number of pages9
JournalDrug Development Research
Issue number2-3
Publication statusPublished - Sep 26 2001


  • Immunomodulation
  • Inflammation
  • Macrophage
  • Purinergic
  • Release

ASJC Scopus subject areas

  • Drug Discovery

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