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Biochim Biophys Acta. 2015 Nov;1851(11):1442-9. doi: 10.1016/j.bbalip.2015.08.009. Epub 2015 Aug 29.

Electronegative LDL induces priming and inflammasome activation leading to IL-1β release in human monocytes and macrophages.

Author information

1
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona (Spain). C/Sant Antoni M. Claret, 167 08025 Barcelona, Spain. Electronic address: mestruch@santpau.cat.
2
Wihuri Research Institute (WRI). Haartmaninkatu, 8 FI-00290 Helsinki, Finland. Electronic address: kristiina.rajamaki@helsinki.fi.
3
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona (Spain). C/Sant Antoni M. Claret, 167 08025 Barcelona, Spain; Molecular Biology and Biochemistry Department, Universitat Autònoma de Barcelona (UAB) Faculty of Medicine, Building M. Cerdanyola del Vallès, Spain. Electronic address: jsanchezq@santpau.cat.
4
Wihuri Research Institute (WRI). Haartmaninkatu, 8 FI-00290 Helsinki, Finland. Electronic address: petri.kovanen@wri.fi.
5
Wihuri Research Institute (WRI). Haartmaninkatu, 8 FI-00290 Helsinki, Finland. Electronic address: kati.oorni@wri.fi.
6
Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona (Spain). C/Sant Antoni M. Claret, 167 08025 Barcelona, Spain; Molecular Biology and Biochemistry Department, Universitat Autònoma de Barcelona (UAB) Faculty of Medicine, Building M. Cerdanyola del Vallès, Spain. Electronic address: sbenitez@santpau.cat.
7
Molecular Biology and Biochemistry Department, Universitat Autònoma de Barcelona (UAB) Faculty of Medicine, Building M. Cerdanyola del Vallès, Spain; Biochemistry Department. Hospital de la Santa Creu i Sant Pau Barcelona. C/Sant Quintí, 89 08026, Barcelona, Spain. Electronic address: jordonez@santpau.cat.

Abstract

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-1β 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-1β release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1β release induced by LDL(−) than by native LDL. LDL(−)-induced IL-1β release involved activation of the CD14-TLR4 receptor complex. LDL(−) induced priming, the first step of IL-1β release, since it increased the transcription of pro-IL-1β (8-fold) and NLRP3 (3-fold) compared to native LDL. Several findings show that LDL(−) induced inflammasome activation, the second step necessary for IL-1β release. Preincubation of monocytes with K+ channel inhibitors decreased LDL(−)-induced IL-1β release. LDL(−) induced formation of the NLRP3-ASC complex. LDL(−) triggered 2-fold caspase-1 activation compared to native LDL and IL-1β release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(−) promoted IL-1β release, which was also associated with caspase-1 activation.

CONCLUSIONS:

LDL(−) promotes release of biologically active IL-1β in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation.

SIGNIFICANCE:

By IL-1β release, LDL(−) could regulate inflammation in atherosclerosis.

KEYWORDS:

Caspase-1; Electronegative LDL; Inflammasome; Interleukin-1β; Macrophages; Monocytes

PMID:
26327597
DOI:
10.1016/j.bbalip.2015.08.009
[Indexed for MEDLINE]

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