title: Modified low density lipoprotein stimulates complement C3 expression and secretion via liver X receptor and Toll-like receptor 4 activation in human macrophages.
abstract: Complement C3 is a pivotal component of three cascades of complement activation. C3 is expressed in human atherosclerotic lesions and is involved in atherogenesis. However, the mechanism of C3 accumulation in atherosclerotic lesions is not well elucidated. We show that acetylated low density lipoprotein and oxidized low density lipoprotein (oxLDL) increase C3 gene expression and protein secretion by human macrophages. Modified LDL (mLDL)-mediated activation of C3 expression mainly depends on liver X receptor (LXR) and partly on Toll-like receptor 4 (TLR4), whereas C3 secretion is increased due to TLR4 activation by mLDL. LXR agonist TO901317 stimulates C3 gene expression in human monocyte-macrophage cells but not in human hepatoma (HepG2) cells. We find LXR-responsive element inside of the promoter region of the human C3 gene, which binds to LXRβ in macrophages but not in HepG2 cells. We show that C3 expression and secretion is decreased in IL-4-treated (M2) and increased in IFNγ/LPS-stimulated (M1) human macrophages as compared with resting macrophages. LXR agonist TO901317 potentiates LPS-induced C3 gene expression and protein secretion in macrophages, whereas oxLDL differently modulates LPS-mediated regulation of C3 in M1 or M2 macrophages. Treatment of human macrophages with anaphylatoxin C3a results in stimulation of C3 transcription and secretion as well as increased oxLDL accumulation and augmented oxLDL-mediated up-regulation of the C3 gene. These data provide a novel mechanism of C3 gene regulation in macrophages and suggest new aspects of cross-talk between mLDL, C3, C3a, and TLR4 during development of atherosclerotic lesions.
authors.affiliation: Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg 197376, Russia. denis@iem.sp.ru
authors.forename: Denis A
authors.initials: DA
authors.lastname: Mogilenko
authors.forename: Igor V
authors.initials: IV
authors.lastname: Kudriavtsev
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Trulioff
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Shavva
authors.forename: Ella B
authors.initials: EB
authors.lastname: Dizhe
authors.forename: Boris V
authors.initials: BV
authors.lastname: Missyul
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Zhakhov
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Ischenko
authors.forename: Andrej P
authors.initials: AP
authors.lastname: Perevozchikov
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
mesh_terms: D001483:Base Sequence; D001692:Biological Transport; D003176:Complement C3 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D000071518:Liver X Receptors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D003176:Complement C3; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D051197:Toll-Like Receptor 4; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein