title: ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage.
abstract: Interleukin (IL)-1beta and IL-18 are structurally similar proteins that require caspase-1 processing for activation. Both proteins are released from the cytosol by unknown pathway(s). To better characterize the release pathway(s) for IL-1beta and IL-18 we evaluated the role of lipopolysaccharide priming, of interleukin-1beta-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-1beta and IL-18 after exogenous ATP. Despite its constitutive cytosolic presence, IL-18 required lipopolysaccharide priming for the ATP-induced release. Neither IL-1beta 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 IL-1beta/IL-18. Taken together, these results suggest that, although synthesis of IL-1beta and IL-18 differ, ATP-mediated release of both cytokines requires a priming step but not proteolytically functional caspase-1.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute and Pulmonary and Critical Care Division, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: V B
authors.initials: VB
authors.lastname: Mehta
authors.forename: J
authors.initials: J
authors.lastname: Hart
authors.forename: M D
authors.initials: MD
authors.lastname: Wewers
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006868:Hydrolysis; D007375:Interleukin-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D020032:Tyrphostins; C069028:AG 127; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D020170:Caspase 1