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P2X7 receptor polymorphism impairs extracellular adenosine 5'-triphosphate-induced interleukin-18 release from human

R Sluyter1, J G Dalitz, J S Wiley

  • 1Department of Medicine, University of Sydney at Nepean Hospital, Penrith NSW 2750, Australia. rons@med.usyd.edu.au

Genes and Immunity
|August 13, 2004
PubMed

Insights

A common genetic variation in the P2X7 receptor (P2RX7) significantly reduces the release of the inflammatory cytokine interleukin-18 (IL-18) in response to adenosine triphosphate (ATP). This impaired IL-18 release is linked to reduced P2X7 receptor function.

Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • Interleukin-18 (IL-18) is a key proinflammatory cytokine.
  • Its release from monocytes is triggered by extracellular adenosine triphosphate (ATP) via the P2X7 receptor.
  • A loss-of-function polymorphism in the human P2X7 receptor (E496A) may affect this process.

Purpose of the Study:

  • To investigate the impact of the P2X7 receptor E496A polymorphism on ATP-induced IL-18 release.
  • To assess the functional consequences of this polymorphism on P2X7 receptor activity.

Main Methods:

  • Whole blood assays were used to measure ATP-induced IL-18 release.
  • Lipopolysaccharide (LPS)-primed monocytes were utilized to study IL-18 release and ethidium uptake.
  • P2X7 receptor surface expression was quantified.

Main Results:

  • Homozygous subjects for the P2X7 receptor E496A polymorphism showed significantly reduced ATP-induced IL-18 release (42% of wild-type in whole blood).
  • In LPS-primed monocytes, ATP-induced IL-18 release was markedly lower in homozygous subjects (21-44% of wild-type).
  • ATP-induced ethidium uptake and P2X7 surface expression were also diminished in homozygous subjects.

Conclusions:

  • The P2X7 receptor E496A polymorphism impairs ATP-mediated IL-18 release from monocytes.
  • This genetic variation leads to reduced P2X7 receptor function and downstream inflammatory signaling.
  • Findings highlight the role of P2X7 receptor genetics in regulating IL-18 production.

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