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Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms

Reza D Beigi1, Sylvia B Kertesy, Gretchen Aquilina

  • 1Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.

British Journal of Pharmacology
|October 3, 2003
PubMed

Insights

Periodate-oxidized ATP (oATP) reduces inflammation by inhibiting pro-inflammatory signaling in cells lacking P2X7 receptors. These findings reveal novel anti-inflammatory mechanisms of oATP beyond P2X7 receptor antagonism.

Area of Science:

  • Biochemistry
  • Immunology
  • Cell Biology

Background:

  • Periodate-oxidized ATP (oATP) is known to antagonize the P2X7 nucleotide receptor (P2X7R), a key mediator of inflammatory signaling.
  • The precise mechanisms by which oATP exerts its anti-inflammatory effects, particularly independent of P2X7R, remain incompletely understood.

Purpose of the Study:

  • To investigate the anti-inflammatory effects of oATP in cell types that do not express P2X7R.
  • To elucidate potential P2X7R-independent mechanisms of oATP-mediated attenuation of pro-inflammatory responses.

Main Methods:

  • Assessed the impact of oATP on the secretion of inflammatory cytokines (IL-8, IL-1beta) stimulated by TNF-alpha, IL-1beta, and endotoxin in human umbilical vein endothelial cells (HUVEC), HEK293 cells, and 1321N1 astrocytes.
  • Evaluated the effect of oATP on nuclear factor-kappaB (NF-kappaB) reporter gene expression and IkappaB degradation.
  • Investigated the influence of oATP on P2Y2 and P2Y1 receptor activity and ecto-ATPase activity.

Main Results:

  • oATP significantly reduced the secretion of IL-8 and IL-1beta in P2X7R-negative cells, with effects comparable to those in P2X7R-expressing cells.
  • oATP attenuated cytokine-induced NF-kappaB reporter gene expression but did not alter IkappaB degradation.
  • While oATP affected P2Y1 receptor function, specific P2Y1 receptor inhibition did not replicate oATP's anti-inflammatory effects. oATP also inhibited ecto-ATPase activity in 1321N1 astrocytes.

Conclusions:

  • oATP possesses potent anti-inflammatory properties that are independent of P2X7R expression or activation.
  • The anti-inflammatory actions of oATP may involve mechanisms beyond direct P2 receptor modulation, including the inhibition of ecto-ATPase activity.

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