ATP treatment of human monocytes promotes caspase-1 maturation and externalization

Mechanisms that regulate conversion of prointerleukin-1 beta (pro-IL-1 beta) to its mature form by the cysteine protease caspase-1 are not well understood. In this study, we demonstrate that mature caspase-1 subunits are produced when human monocytes are treated with ATP and, like mature IL-1 beta, are released extracellularly. Characterization of the pharmacological sensitivity of this stimulus coupled response revealed that some caspase-1 inhibitors allow pro-IL-1 beta secretion, whereas others do not. Two nonselective alkylating agents, N-ethylmaleimide and phenylarsine oxide, also blocked maturation and release of pro-IL-1 beta. Two inhibitors of anion transport, glyburide and ethacrynic acid, blocked maturation of both caspase-1 and pro-IL-1 beta and prevented release of the propolypeptides, Procaspase-3 was detected in monocyte extracts, but its proteolytic activation was not efficient in the presence of ATP, Maturation of procaspase-1 and release of the mature enzyme subunits therefore accompany stimulus-coupled human monocyte IL-1 post-translational processing. Agents that appear to selectively inhibit mature caspase-1 do not prevent ATP-treated cells from releasing their cytosolic components, On the other hand, anion transport inhibitors and alkylating agents arrest ATP-treated monocytes in a state where membrane latency is maintained. The data provided support the hypothesis that stimulus-coupled IL-1 post-translational processing involves a commitment to cell death.