Cell death is not essential for caspase-1-mediated interleukin-1β activation and secretion

Stephanie A. Conos, K. E. Lawlor, D. L. Vaux, James E Vince, L. M. Lindqvist

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1827-1838
Number of pages12
JournalCell Death and Differentiation
Volume23
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016
Externally publishedYes

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