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Altered cytokine production in mice lacking P2X(7) receptors.

The P2X(7) receptor (P2X(7)R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1 beta post-translational processing, we have generated a P2X(7)R-deficient mouse line. P2X(7)R(-/-) macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1 beta comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1 beta produced by the P2X(7)R(-/-) cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1 beta from P2X(7)R(-/-) macrophages. In response to in vivo lipopolysaccharide injection, both wild-type and P2X(7)R(-/-) animals display increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subsequent ATP injection to wild-type animals promotes an increase in IL-1, which in turn leads to additional IL-6 production; similar increases did not occur in ATP-treated, LPS-primed P2X(7)R(-/-) animals. Absence of the P2X(7)R thus leads to an inability of peritoneal macrophages to release IL-1 in response to ATP. As a result of the IL-1 deficiency, in vivo cytokine signaling cascades are impaired in P2X(7)R-deficient animals. Together these results demonstrate that P2X(7)R activation can provide a signal that leads to maturation and release of IL-1 beta and initiation of a cytokine cascade.

Pubmed ID: 11016935


  • Solle M
  • Labasi J
  • Perregaux DG
  • Stam E
  • Petrushova N
  • Koller BH
  • Griffiths RJ
  • Gabel CA


The Journal of biological chemistry

Publication Data

January 5, 2001

Associated Grants


Mesh Terms

  • Adenosine Triphosphate
  • Animals
  • Cells, Cultured
  • Cyclooxygenase 2
  • Enzyme Induction
  • Fluorescent Dyes
  • Gene Deletion
  • Gene Targeting
  • Inflammation
  • Interleukin-1
  • Interleukin-6
  • Isoenzymes
  • Lipopolysaccharides
  • Macrophages, Peritoneal
  • Mice
  • Mice, Knockout
  • Nigericin
  • Prostaglandin-Endoperoxide Synthases
  • Protein Precursors
  • Protein Processing, Post-Translational
  • Purinergic P2 Receptor Agonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X7