title: Endogenous apolipoprotein A-I stabilizes ATP-binding cassette transporter A1 and modulates Toll-like receptor 4 signaling in human macrophages.
abstract: Apolipoprotein A-I (ApoA-I) is the main functional protein component of human high-density lipoproteins. ApoA-I shows various anti-inflammatory and atheroprotective properties toward macrophages; however, endogenous apoA-I expression has not been investigated in macrophages. We have shown that endogenous apoA-I gene is expressed in human macrophages at both mRNA and protein levels. Endogenous ApoA-I is localized in intracellular vesicles and at the external side of the plasma membrane in association with ATP-binding cassette transporter A1 (ABCA1) and lipid rafts in macrophages. We have shown that endogenous ApoA-I stabilizes ABCA1, moreover, down-regulation of ApoA-I by siRNA results in an increase of Toll-like receptor 4 (TLR4) mRNA and membrane surface protein expression, as well as an enhancement of bacterial lipopolysaccharide (LPS)-induced expression of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and inducible nitric oxide synthase (NOS2) genes in human macrophages. TNF-α stimulates ApoA-I expression and secretion (1.2±0.2 vs. 4.3±0.9 ng/mg total protein) in macrophages. Obtained results suggest that endogenous ApoA-I has anti-inflammatory properties, presumably due to ABCA1 stabilization in macrophages; these results elucidate the cell type-specific mechanism of the TNF-α-mediated regulation of apoA-I gene expression in monocytes and macrophages.
authors.affiliation: Institute of Experimental Medicine, Russian Academy of Medical Sciences, Department of Biochemistry, Acad. Pavlov St., 12, St. Petersburg, 197376, Russia. denis@iem.sp.ru
authors.forename: Denis A
authors.initials: DA
authors.lastname: Mogilenko
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Trulioff
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Ivanov
authors.forename: Vadim K
authors.initials: VK
authors.lastname: Nagumanov
authors.forename: Igor V
authors.initials: IV
authors.lastname: Kudriavtsev
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Shavva
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Tanyanskiy
authors.forename: Andrej P
authors.initials: AP
authors.lastname: Perevozchikov
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D017931:DNA Primers; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4