| The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro. | |
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MedLine Citation:
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PMID: 20410491 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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TNF-like protein 1A (TL1A), a TNF superfamily cytokine that binds to death receptor 3 (DR3), is highly expressed in macrophage foam cell-rich regions of atherosclerotic plaques, although its role in foam cell formation has yet to be elucidated. We investigated whether TL1A can directly stimulate macrophage foam cell formation in both THP-1 and primary human monocyte-derived macrophages with the underlying mechanisms involved. We demonstrated that TL1A promotes foam cell formation in human macrophages in vitro by increasing both acetylated and oxidized low-density lipoprotein uptake, by enhancing intracellular total and esterified cholesterol levels and reducing cholesterol efflux. This imbalance in cholesterol homeostasis is orchestrated by TL1A-mediated changes in the mRNA and protein expression of several genes implicated in the uptake and efflux of cholesterol, such as scavenger receptor A and ATP-binding cassette transporter A1. Furthermore, through the use of virally delivered DR3 short-hairpin RNA and bone marrow-derived macrophages from DR3 knockout mice, we demonstrate that DR3 can regulate foam cell formation and contributes significantly to the action of TL1A in this process in vitro. We show, for the first time, a novel proatherogenic role for both TL1A and DR3 that implicates this pathway as a target for the therapeutic intervention of atherosclerosis. |
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Authors:
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James E McLaren; Claudia J Calder; Brian P McSharry; Keith Sexton; Rebecca C Salter; Nishi N Singh; Gavin W G Wilkinson; Eddie C Y Wang; Dipak P Ramji |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-04-21 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 184 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-20 Completed Date: 2010-07-19 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 5827-34 Citation Subset: AIM; IM |
Affiliation:
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Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atherosclerosis / immunology, pathology Biological Transport / immunology Cell Differentiation / immunology* Cell Line, Tumor Cells, Cultured Cholesterol Ester Transfer Proteins / antagonists & inhibitors, metabolism Female Foam Cells / cytology*, immunology*, pathology Humans Intracellular Fluid / immunology, metabolism Lipoproteins, LDL / metabolism Mice Mice, Knockout Receptors, Tumor Necrosis Factor, Member 25 / deficiency, physiology* Signal Transduction / immunology* Tumor Necrosis Factor Ligand Superfamily Member 15 / physiology* Up-Regulation / immunology |
| Grant Support | |
ID/Acronym/Agency:
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BBF0098361//Biotechnology and Biological Sciences Research Council; G0300180//Medical Research Council; G0300180(65735)//Medical Research Council; G0700142//Medical Research Council; G0901119(91900)//Medical Research Council; GR07075//Wellcome Trust; PG/07/031/22716//British Heart Foundation |
| Chemical | |
Reg. No./Substance:
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0/Cholesterol Ester Transfer Proteins; 0/Lipoproteins, LDL; 0/Receptors, Tumor Necrosis Factor, Member 25; 0/TNFSF15 protein, human; 0/Tumor Necrosis Factor Ligand Superfamily Member 15 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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