Human monocyte stimulus-coupled IL-1β posttranslational processing: modulation via monovalent cations

Abstract

Lipopolysaccharide-activated human monocytes produce prointerleukin (pro-IL)-1β 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-1β processing. Titration of NaCl into choline chloride- or sucrose-based media restored 17-kDa IL-1β production. Na+replacement, however, was not sufficient to support ATP-induced production of 17-kDa IL-1β 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-1β posttranslational processing, therefore, requires extracellular Na+for a step downstream of the initiating stimulus but preceding caspase-1 activation.