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. 2007 Mar 1;120(Pt 5):772-81.
doi: 10.1242/jcs.03377. Epub 2007 Feb 6.

Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death

David Brough  1 , Nancy J Rothwell
Affiliations

Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death

David Brough et al. J Cell Sci. .

Abstract

The pro-inflammatory cytokine interleukin-1beta is a key mediator of inflammation and is implicated in the pathogenesis of diverse disease states. Despite its biological importance, the mechanisms of its processing to an active form and its trafficking to the extracellular compartment remain poorly understood. Interleukin-1beta secretion is proposed to occur via several distinct mechanisms including microvesicle shedding and the regulated secretion of lysosomes. In this study, we report for the first time that caspase-1-dependent processing of pro-interleukin-1beta can occur in the cytosol following activation of P2X7-receptor. We also provide evidence that the pathway of secretion in this model is independent of the lysosomal trafficking regulator, a protein involved in lysosome secretion. Although release of interleukin-1beta occurred before the appearance of significant levels of lactate dehydrogenase in the supernatant, the cells ultimately died. It is clear that structural changes preceding cell death, occurring after caspase-1 activation, promote the cellular release of interleukin-1beta. We investigated the involvement of lipid rafts in this process and discovered that depleting the plasma membrane of cholesterol did not adversely affect interleukin-1beta secretion in response to ATP. We propose that, in macrophages, ATP-induced interleukin-1beta processing occurs in the cytosol by a mechanism that resembles pyroptosis.

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