ATP-stimulated release of interleukin (IL)-1β and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage

Interleukin (IL)-1 beta and IL-18 are structurally similar proteins that require caspase-1 processing for activation. Both proteins are released hom the cytosol by unknown pathway(s). To better characterize the release pathway(s) for IL-1 beta and IL-18 we evaluated the role of lipopolysaccharide priming, of interleukin-1 beta -converting enzyme (ICE) inhibition, of human purinergic receptor (P2X(7) function, and of signaling pathways in human monocytes induced by ATP. Monocytes rapidly processed and released both IL-1 beta and IL-18 after exogenous ATP. Despite its constitutive cytosolic presence, IL-18 required lipopolysaccharide priming for the ATP-induced release. Neither IL-1 beta nor IL-18 release was prevented by ICE inhibition, and IL-18 release was not induced by ICE activation itself. Release of both cytokines was blocked completely by a P2X7 receptor antagonist, oxidized ATP, and partially by an antibody to P2X(7), receptor. In evaluating the signaling components involved in the ATP effect, we identified that the protein-tyrosine kinase inhibitor, AG126, produced a profound inhibition of both ICE activation as well as release of IG1 beta /IL-18 Taken together, these results suggest that, although synthesis of IL-1 beta and IL-18 differ, ATP-mediated release of both cytokines requires a priming step but not proteolytically functional caspase-1.