title: ATP treatment of human monocytes promotes caspase-1 maturation and externalization.
abstract: Mechanisms that regulate conversion of prointerleukin-1beta (pro-IL-1beta) 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-1beta, are released extracellularly. Characterization of the pharmacological sensitivity of this stimulus-coupled response revealed that some caspase-1 inhibitors allow pro-IL-1beta secretion, whereas others do not. Two nonselective alkylating agents, N-ethylmaleimide and phenylarsine oxide, also blocked maturation and release of pro-IL-1beta. Two inhibitors of anion transport, glyburide and ethacrynic acid, blocked maturation of both caspase-1 and pro-IL-1beta 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.
authors.affiliation: Department of Respiratory, Pfizer Central Research, Groton, Connecticut 06340, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Laliberte
authors.forename: J
authors.initials: J
authors.lastname: Eggler
authors.forename: C A
authors.initials: CA
authors.lastname: Gabel
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D001152:Arsenicals / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005033:Ethylmaleimide / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000201:enzymology*; D011499:Protein Processing, Post-Translational
chemical_list: D001152:Arsenicals; D061945:Caspase Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; C029341:oxophenylarsine; D000255:Adenosine Triphosphate; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1; D005033:Ethylmaleimide