Altered cytokine production in mice lacking P2X(7) receptors

The P2X(7) receptor (P2X(7)R) is an ATP-gated ion channel expressed by mono cytes and macrophages, To directly address the role of this receptor in int erleukin (IL)-1 beta post-translational processing, we have generated a P2X (7)R-deficient mouse line. P2X(7)R(-/-) macrophages respond to lipopolysacc haride 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-I L-1 beta produced by the P2X(7)R(-/-) cells is not externalized or activate d by caspase-1, Nigericin, an alternate secretion stimulus, promotes releas e 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 disp lay increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subs equent ATP injection to wild-type animals promotes an increase in IL-1, whi ch in turn leads to additional IL-6 production; similar increases did not o ccur 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 r esponse to ATP. As a result of the IL-1 deficiency, in vivo cytokine signal ing cascades are impaired in P2X(7)R-deficient animals. Together these resu lts 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.