期刊
JOURNAL OF CELL SCIENCE
卷 120, 期 5, 页码 772-781出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.03377
关键词
interleukin-1; cathepsin D; caspase-1; pyroptosis; membrane fluidity
类别
资金
- Medical Research Council [G9219675] Funding Source: researchfish
- MRC [G9219675] Funding Source: UKRI
- Medical Research Council [G9219675] Funding Source: Medline
The pro-inflammatory cytokine interleukin-1 beta 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-1 beta 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 prointerleukin-1 beta 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-1 beta 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-1 beta. We investigated the involvement of lipid rafts in this process and discovered that depleting the plasma membrane of cholesterol did not adversely affect interleukin-1 beta secretion in response to ATP. We propose that, in macrophages, ATP-induced interleukin-1 beta processing occurs in the cytosol by a mechanism that resembles pyroptosis.
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