Interleukin-1 beta posttranslational processing - Exploration of P2X(7) receptor involvement

Cultured monocytes and macrophages stimulated with LPS produce large quanti ties of prointerleukin (IL)-1 beta, but release little mature cytokine to t he medium. The efficiency at which the procytokine is converted to its acti ve 17 kDa species and released extracellularly is enhanced by treating cyto kine-producing cells with a secretion stimulus such as ATP or nigericin. Al terations to the composition of the intracellular ionic environment, includ ing a necessary K+ efflux, accompany the stimulus-induced secretory process . Cell death also accompanies stimulus-induced IL-1 posttranslational proce ssing and human monocytes treated with ATP generate and release mature casp ase-1. ATP-treated monocytes achieve a swollen morphology and do not produc e mature caspase-3; these traits are uncharacteristic of an apoptotic mecha nism. Stimulus-induced secretion of IL-1 beta is disrupted by substitution of medium Cl- with chaotropic anions such as l(-) and by numerous anion tra nsport inhibitors. These pharmacological agents block processing independen tly of the nature of the secretion stimulus, suggesting that a common downs tream mechanism is engaged. Although sufficient to activate, the P2X(7) rec eptor (P2X(7)R) is not a necessary element of the secretory mechanism. KN-6 2, an antagonist of P2X7R function, inhibits ATP-induced IL-1 beta posttran slational processing but does not inhibit processing induced by nigericin. Likewise, LPS-activated peritoneal macrophages isolated from P2X(7)R-defici ent mice respond to nigericin and produce mature 17 kDa IL-1 beta. On the o ther hand, the receptor-deficient macrophages, in contrast to their wild-ty pe counterparts, do not respond to ATP. These findings highlight the unusua l secretory requirements of IL-1 and demonstrate that P2X7R activation repr esents one mechanism by Which cytokine posttranslational processing can be initiated. (C) 2001 Wiley-Liss, Inc.