title: Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms.
abstract: 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.
authors.affiliation: Research Institute for Internal Medicine, The National Hospital, Oslo, Norway. bente.halvorsen@klinmed.uio.no
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Torgun
authors.initials: T
authors.lastname: Waehre
authors.forename: Hanne
authors.initials: H
authors.lastname: Scholz
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Clausen
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Müller
authors.forename: Hilde
authors.initials: H
authors.lastname: Heimli
authors.forename: Serena
authors.initials: S
authors.lastname: Tonstad
authors.forename: Christian
authors.initials: C
authors.lastname: Hall
authors.forename: Stig S
authors.initials: SS
authors.lastname: Frøland
authors.forename: Erik A
authors.initials: EA
authors.lastname: Biessen
authors.forename: Jan Kristian
authors.initials: JK
authors.lastname: Damås
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D017209:Apoptosis; D001161:Arteriosclerosis; D001391:Azo Compounds / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010100:Oxygen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D001391:Azo Compounds; C096816:BCL2-related protein A1; D008077:Lipoproteins, LDL; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C099252:oxidized low density lipoprotein; D016753:Interleukin-10; C011049:oil red O; D010100:Oxygen