Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1851, Issue 11, Pages 1442-1449Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2015.08.009
Keywords
Electronegative LDL; Interleukin-1 beta; Inflammasome; Caspase-1; Monocytes; Macrophages
Funding
- Fondo de Investigacion Sanitaria [FIS PI12/00967, FIS PI13/00364]
- Academy of Finland [265940]
- Finninsh Foundation for Cardiovascular Research
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Background: Electronegative LDL (LDL(-)), a modified LDL fraction found in blood, induces the release of inflammatory mediators in endothelial cells and leukocytes. However, the inflammatory pathways activated by LDL(-) have not been fully defined. We aim to study whether LDL(-) induced release of the first-wave proinflammatory IL-1 beta in monocytes and monocyte-derived macrophages (MDM) and the mechanisms involved. Methods: LDL(-) was isolated from total LDL by anion exchange chromatography. Monocytes and MDM were isolated from healthy donors and stimulated with LDL(+) and LDL(-) (100 mg apoB/L). Results: In monocytes, LDL(-) promoted IL-1 beta release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1 beta release induced by LDL(-) than by native LDL LDL(-)-induced IL-1 beta release involved activation of the CD14-TLR4 receptor complex. LDL(-) induced priming, the first step of IL-1 beta release, since it increased the transcription of pro-IL-1 beta (8-fold) and NLRP3 (3-fold) compared to native LDL Several findings show that LDL(-) induced inflammasome activation, the second step necessary for IL-1 beta release. Preincubation of monocytes with K+ channel inhibitors decreased LDL(-)-induced IL-1 beta release. LDL(-) induced formation of the NLRP3-ASC complex. LDL(-) triggered 2-fold caspase-1 activation compared to native LDL and IL-1 beta release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(-) promoted IL-1 beta release, which was also associated with caspase-1 activation. Conclusions: LDL(-) promotes release of biologically active IL-1 beta in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation. Significance: By IL-1 beta release, LDL(-) could regulate inflammation in atherosclerosis. (C) 2015 Elsevier B.V. All rights reserved.
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