title: Human monocyte stimulus-coupled IL-1beta posttranslational processing: modulation via monovalent cations.
abstract: Lipopolysaccharide-activated human monocytes produce prointerleukin (pro-IL)-1beta but release little of this inflammatory cytokine as the biologically active species. Efficient externalization of mature 17-kDa cytokine requires that the activated monocytes encounter a secondary stimulus such as ATP. To identify cation requirements of the ATP-induced process, lipopolysaccharide-activated monocytes were treated with ATP in media containing different Cl- salts or sucrose. Media devoid of Na+ did not support IL-1beta processing. Titration of NaCl into choline chloride- or sucrose-based media restored 17-kDa IL-1beta production. Na+ replacement, however, was not sufficient to support ATP-induced production of 17-kDa IL-1beta in the presence of >/=37 mM extracellular K+ or Li+. Inhibition by K+ suggests that efflux of this cation is a necessary component of the stimulus-coupled response. The inhibitory effect achieved by Na+ depletion is not due to inactivation of the ATP receptor and is distinct from a caspase-1 inhibitor. Stimulus-coupled IL-1beta posttranslational processing, therefore, requires extracellular Na+ for a step downstream of the initiating stimulus but preceding caspase-1 activation.
authors.affiliation: Pfizer Central Research, Groton, Connecticut 06340, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Perregaux
authors.forename: C A
authors.initials: CA
authors.lastname: Gabel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D002414:Cations, Monovalent / Q000494:pharmacology; D016922:Cellular Senescence / Q000502:physiology; D003470:Culture Media / Q000737:chemistry; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D012964:Sodium / Q000494:pharmacology
chemical_list: D002414:Cations, Monovalent; D003470:Culture Media; D007375:Interleukin-1; C546468:P2RX7 protein, human; D011498:Protein Precursors; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D012964:Sodium