Journal article

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

SA Conos, KE Lawlor, DL Vaux, JE Vince, LM Lindqvist

CELL DEATH AND DIFFERENTIATION | NATURE PUBLISHING GROUP | Published : 2016

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, ..

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Grants

Awarded by National Health and Medical Research (Canberra, Australia)


Awarded by Victorian State Government OIS


Funding Acknowledgements

We thank W Cook and J Silke (WEHI) for vectors, M Rashidi (WEHI) for NF-kappa B Thp1 reporter cells, K Schroder (IMB) for the pMIGR retroviral vector and R Lewis (WEHI) for cloning the IL-1 beta vector. This work was supported by National Health and Medical Research (Canberra, Australia) Project grants (1051210, 1101405), fellowships (JEV (1052598); LL (1035502); DLV (1020136)) and Program Grants (461221), and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS (361646). We thank R Crawley for animal care; S Monard and staff for cell sorting; M Hardy for assistance with ELISpots; L Whitehead for assistance with image acquisition.