Abstract
© 2015 Elsevier B.V. All rights reserved. Background: Electronegative LDL (LDL(-)), a modified LDL fraction found in blood, induces the release of inflammatorymediators in endothelial cells and leukocytes. However, the inflammatory pathways activated by LDL(-) have not been fully defined.Weaimto study whether LDL(-) induced release of the first-wave proinflammatory IL-1ß 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: Inmonocytes, LDL(-) promoted IL-1ß release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1ß release induced by LDL(-) than by native LDL. LDL(-)-induced IL-1ß release involved activation of the CD14-TLR4 receptor complex. LDL(-) induced priming, the first step of IL-1ß release, since it increased the transcription of pro-IL-1ß (8-fold) and NLRP3 (3-fold) compared to native LDL. Several findings show that LDL(-) induced inflammasome activation, the second step necessary for IL-1ß release. Preincubation ofmonocytes with K+ channel inhibitors decreased LDL(-)-induced IL-1ß release. LDL(-) induced formation of the NLRP3-ASC complex. LDL(-) triggered 2-fold caspase-1 activation compared to native LDL and IL-1ß release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(-) promoted IL-1ß release, which was also associated with caspase-1 activation. Conclusions: LDL(-) promotes release of biologically active IL-1ß inmonocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation. Significance: By IL-1ß release, LDL(-) could regulate inflammation in atherosclerosis.
Original language | English |
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Pages (from-to) | 1442-1449 |
Journal | Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids |
Volume | 1851 |
Issue number | 11 |
DOIs | |
Publication status | Published - 4 Nov 2015 |
Keywords
- Caspase-1
- Electronegative LDL
- Inflammasome
- Interleukin-1ß
- Macrophages
- Monocytes