Copyright © 2005, European Society of Cardiology
Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10
Institute for Prophylaxis of Cardiovascular Diseases, University of Munich, Germany, Pettenkoferstr. 9, D-80336 Munich, Germany
* Corresponding author. Tel.: +49 89 5160 4350; fax: +49 89 5160 4352. Email address: trubic{at}web.de, www.kreislaufinstitut.de
Objective: Marked anti-atheromatous effects of the anti-inflammatory cytokine interleukin-10 (IL-10) were observed in several lipid-driven animal models of arteriosclerosis. We therefore investigated whether IL-10 affects macrophage cholesterol handling.
Methods: Human THP-1 cells and peripheral monocytes served as macrophage models. Specific mRNA was quantified by real-time RT-PCR, protein expression by flow cytometry and Western blotting. Cellular cholesterol handling was studied by lipoprotein-facilitated uptake and efflux assays. IL-10 effects were also studied in cells transfected with liver X receptor alpha (LXR
)-siRNA or a LXR response element (LXRE) reporter construct.
Results: Picomolar IL-10 suppressed basal and peroxisome proliferator-activated receptor gamma (PPAR
)-stimulated transcription of the scavenger receptor CD36 due to reduced PPAR protein expression. In contrast, IL-10 stimulated transcription of the active cellular cholesterol exporters ATP-binding cassette transporters A1 and G1 (ABCA1, ABCG1) and the LDL receptor, whereas scavenger receptor-BI (SR-BI) was unchanged. The reduction of CD36 and stimulation of ABCA1 expression was confirmed in human monocytes. Thereby, IL-10 prevented cellular cholesterol overloading from oxidized LDL (oxLDL) and enhanced efflux to apoA-containing particles initiating reverse cholesterol transport. Experiments with inhibitors, LXR silencing and the LXRE reporter gene construct supported the proximal transmission of the IL-10 effect on ABCA1 by the IL-10 receptor/signal transducer and activator of transcription 3 (STAT3) pathway and distal cross-talk to the LXR and PPAR/retinoic acid X receptor (RXR) and cAMP/protein kinase A (PKA) pathways.
Conclusions: In addition to immune and anti-inflammatory actions, IL-10 redirects macrophage cholesterol handling towards reverse cholesterol transport, which contributes to its anti-atherosclerotic action.
KEYWORDS Cytokines; CD36; ABCA1; Reverse cholesterol transport; Atherosclerosis
Time for primary review 16 days
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