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Journal of Lipid Research, Vol. 46, 211-219, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology
* Research Institute for Internal Medicine, The National Hospital, Oslo, Norway
Department of Cardiology, The National Hospital, Oslo, Norway
Institute of Pathology, The National Hospital, Oslo, Norway
Institute of Microbiology, The National Hospital, Oslo, Norway
Section of Clinical Immunology and Infectious Diseases, The National Hospital, Oslo, Norway
Institute for Nutrition Research, Ullevål University Hospital, University of Oslo, Oslo, Norway
*** Preventive Cardiology, Ullevål University Hospital, University of Oslo, Oslo, Norway
** Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research and the Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands
1 To whom correspondence should be addressed. e-mail: bente.halvorsen{at}klinmed.uio.no
Interleukin (IL)-10 may have a therapeutic potential in atherosclerosis, but its mechanisms of action have not been clarified. Foam cell formation is a key event in atherogenesis, and apoptosis of these lipid-laden cells may promote plaque destabilization. We sought to explore whether IL-10 could have plaque-stabilizing properties in acute coronary syndromes (ACS). We studied the effect of IL-10 on oxidized low density lipoprotein (oxLDL)-stimulated THP-1 cells and monocyte-derived macrophages from ACS patients and healthy controls using different experimental approaches. Our main findings were: i) IL-10 enhances lipid accumulation in oxLDL-stimulated THP-1 macrophages, at least partly by counteracting oxLDL-induced apoptosis; ii) This antiapoptotic effect of IL-10 involves increased expression of the antiapoptotic genes Bfl-1 and Mcl-1, accompanied by protective effects on mitochondria function; iii) By silencing Bfl-1 and Mcl-1 genes using siRNAs, we were able to abolish this IL-10-mediated effect on lipid accumulation; iv) IL-10 also induced lipid accumulation in oxLDL-stimulated macrophages from patients with ACS, but not in macrophages from healthy controls; v) In ACS patients, this enhancing effect of IL-10 on lipid accumulation was accompanied by enhanced Mcl-1 expression. No such antiapoptotic effect was seen in macrophages from healthy controls.
These findings suggest a new mechanism for the effect of IL-10 in atherosclerosis, possibly contributing to plaque stabilization.
Abbreviations: ACS, acute coronary syndromes; CAD, coronary artery disease; CRP, C-reactive protein; IL, interleukin; LOX-1, lectin-like oxLDL receptor-1; oxLDL, oxidized low density lipoprotein; PBMC, peripheral blood mononuclear cell; PI, propidium iodine; PMA, phorbol myristate acetate; RPA, RNase protection assay; TNF, tumor necrosis factor
Supplementary key words foam cell macrophages • acute coronary syndromes • atherosclerosis • apoptosis
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