P2Y6 Nucleotide Receptor Mediates Monocyte Interleukin-8 Production in Response to UDP or Lipopolysaccharide

• Published in: The Journal of biological chemistry 2001-07, Vol.276 (28), p.26051-26056
• Main Authors: Warny, Michel, Aboudola, Samer, Robson, Simon C., Sévigny, Jean, Communi, Didier, Soltoff, Stephen P., Kelly, Ciarán P.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M102568200

Extracellular nucleotides are autocrine and paracrine cellular mediators that signal through P2 nucleotide receptors. Monocytic cells express several P2Y receptors but the role of these G protein-coupled receptors in monocytes is not known. Here, we present evidence that P2Y6 regulates chemokine production and release in monocytes. We find that UDP, a selective P2Y6 agonist, stimulates interleukin (IL)-8 release in human THP-1 monocytic cells whereas other nucleotides are relatively inactive. P2 receptor antagonists or P2Y6 antisense oligonucleotides inhibit IL-8 release induced by UDP. Furthermore, UDP specifically activated IL-8 production in astrocytoma 1321N1 cells transfected with human P2Y6. Since lipopolysaccharide has been suggested to activate P2 receptors via nucleotide release, we tested whether IL-8 production stimulated by lipopolysaccharide might result from P2Y6 activation. P2 antagonists or apyrase, an enzyme which hydrolyzes nucleotides including UDP, inhibit IL-8 production induced by lipopolysaccharide but not by other stimuli. Furthermore, IL-8 gene expression activated by lipopolysaccharide is enhanced by P2Y6 overexpression and inhibited by P2Y6 antisense oligonucleotides. Thus, UDP activates IL-8 production via P2Y6 in monocytic cells. Furthermore, lipopolysaccharide mediates IL-8 production at least in part by autocrine P2Y6 activation. These findings indicate a novel role for P2Y6 in innate immune defenses.