Altered Cytokine Production in Mice Lacking P2X7Receptors*

The P2X7 receptor (P2X7R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1β post-translational processing, we have generated a P2X7R-deficient mouse line.P2X7R −/− macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1β comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1β produced by theP2X7R −/− cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1β fromP2X7R −/− macrophages. In response to in vivo lipopolysaccharide injection, both wild-type andP2X7R −/− 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-primedP2X7R −/− animals. Absence of the P2X7R 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 P2X7R-deficient animals. Together these results demonstrate that P2X7R activation can provide a signal that leads to maturation and release of IL-1β and initiation of a cytokine cascade.