Neutrophil elastase promotes interleukin-1ß secretion from human coronary endothelium.
J Biol Chem
; 290(40): 24067-78, 2015 Oct 02.
Article
em En
| MEDLINE
| ID: mdl-26269588
ABSTRACT
The endothelium is critically involved in the pathogenesis of atherosclerosis by producing pro-inflammatory mediators, including IL-1ß. Coronary arteries from patients with ischemic heart disease express large amounts of IL-1ß in the endothelium. However, the mechanism by which endothelial cells (ECs) release IL-1ß 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-1ß processing and release. This study tested the hypothesis that NE potentiates the processing and release of IL-1ß from human coronary endothelium. We found that NE cleaves the pro-isoform of IL-1ß in ECs and causes significant secretion of bioactive IL-1ß via extracellular vesicles. This release was attenuated significantly by inhibition of neutrophil elastase but not caspase-1. Transient increases in intracellular Ca(2+) levels were observed prior to secretion. Inside ECs, and after NE treatment only, IL-1ß was detected within LAMP-1-positive multivesicular bodies. The released vesicles contained bioactive IL-1ß. In vivo, in experimental atherosclerosis, NE was detected in mature atherosclerotic plaques, predominantly in the endothelium, alongside IL-1ß. This study reveals a novel mechanistic link between NE expression in atherosclerotic plaques and concomitant pro-inflammatory bioactive IL-1ß secretion from ECs. This could reveal additional potential anti-IL-1ß therapeutic targets and provide further insights into the inflammatory process by which vascular disease develops.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Endotélio Vascular
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Regulação Enzimológica da Expressão Gênica
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Elastase de Leucócito
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Vasos Coronários
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Interleucina-1beta
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article