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

      The Journal of Biological Chemistry

      Adenosine Triphosphate, pharmacology, Animals, Cells, Cultured, Cyclooxygenase 2, Enzyme Induction, drug effects, Fluorescent Dyes, metabolism, Gene Deletion, Gene Targeting, Inflammation, genetics, Interleukin-1, biosynthesis, 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, deficiency, physiology, Receptors, Purinergic P2X7

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          Abstract

          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.

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          Journal
          11016935
          10.1074/jbc.M006781200

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