Alfaidi, M., Wilson, H., Daigneault, M. et al. (4 more authors) (2015) Neutrophil Elastase Promotes Interleukin-1 beta Secretion from Human Coronary Endothelium. The Journal of Biological Chemistry, 290. 24067 - 24078. ISSN 0021-9258
Abstract
The endothelium is critically involved in the pathogenesis of atherosclerosis by producing pro-inflammatory mediators, including IL-1β. Coronary arteries from patients with ischemic heart disease express large amounts of IL-1β in the endothelium. However, the mechanism by which endothelial cells (ECs) release IL-1β remains to be elucidated. We investigated neutrophil elastase (NE), a potent serine protease detected in vulnerable areas of human carotid plaques, as a potential “trigger” for IL-1β processing and release. This study tested the hypothesis that NE potentiates the processing and release of IL-1β from human coronary endothelium. We found that NE cleaves the pro-isoform of IL-1β in ECs and causes significant secretion of bioactive IL-1β via extracellular vesicles. This release was attenuated significantly by inhibition of neutrophil elastase but not caspase-1. Transient increases in intracellular Ca2+ levels were observed prior to secretion. Inside ECs, and after NE treatment only, IL-1β was detected within LAMP-1-positive multivesicular bodies. The released vesicles contained bioactive IL-1β. In vivo, in experimental atherosclerosis, NE was detected in mature atherosclerotic plaques, predominantly in the endothelium, alongside IL-1β. This study reveals a novel mechanistic link between NE expression in atherosclerotic plaques and concomitant pro-inflammatory bioactive IL-1β secretion from ECs. This could reveal additional potential anti-IL-1β therapeutic targets and provide further insights into the inflammatory process by which vascular disease develops.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 The American Society for Biochemistry and Molecular Biology. This is an author produced version of a paper subsequently published in Journal of Biological Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | atherosclerosis; endothelium; extracellular vesicles; inflammation; interleukin 1 (IL-1); neutrophil elastase |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Oct 2015 17:39 |
Last Modified: | 24 Oct 2016 19:39 |
Published Version: | http://dx.doi.org/10.1074/jbc.M115.659029 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Refereed: | Yes |
Identification Number: | 10.1074/jbc.M115.659029 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:89570 |