Cell death is not essential for caspase-1-mediated interleukin-1[beta] activation and secretion

• Published in: Cell death and differentiation 2016-11, Vol.23 (11), p.1827
• Main Authors: Conos, S A, Lawlor, K E, Vaux, D L, Vince, J E, Lindqvist, L M
• Format: Article
• Language: English
• Subjects: Cell death
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2016.69

Caspase-1 cleaves and activates the pro-inflammatory cytokine interleukin-1 beta (IL-1β), yet the mechanism of IL-1β release and its dependence on cell death remains controversial. To address this issue, we generated a novel inflammasome independent system in which we directly activate caspase-1 by dimerization. In this system, caspase-1 dimerization induced the cleavage and secretion of IL-1β, which did not require processing of caspase-1 into its p20 and p10 subunits. Moreover, direct caspase-1 dimerization allowed caspase-1 activation of IL-1β to be separated from cell death. Specifically, we demonstrate at the single cell level that IL-1β can be released from live, metabolically active, cells following caspase-1 activation. In addition, we show that dimerized or endogenous caspase-8 can also directly cleave IL-1β into its biologically active form, in the absence of canonical inflammasome components. Therefore, cell death is not obligatory for the robust secretion of bioactive IL-1β.