Tumor necrosis factor-α and lymphotoxin-α increase macrophage ABCA1 by gene expression and protein stabilization via different receptors

  • Kimberly A. Edgel
    Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
    Search for articles by this author
  • Renée C. LeBoeuf
    Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
    Search for articles by this author
  • John F. Oram
    Corresponding author at: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Box 358055, University of Washington, Seattle, WA 98195-8055, United States. Tel.: +1 206 543 3470; fax: +1 206 685 3781.
    Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
    Search for articles by this author



      The tumor necrosis factor superfamily may exert cardioprotective or atherogenic effects, depending on the state of lesion progression. Tumor necrosis factor-α (TNF) induces macrophage ATP-binding cassette transporter A1 (ABCA1), a cardioprotective transmembrane protein that exports cellular cholesterol to apolipoprotein A-I. Here we examined the role of TNF receptors (TNFRs) in ABCA1 induction and tested the effects of lymphotoxin-α (LT), another TNF family member, on macrophage ABCA1 levels.


      Primary macrophages taken from mice deficient in TNF receptors were used to determine ABCA1 expression and cholesterol efflux activity in response to treatment with exogenous TNF or LT.


      We studied TNFR2−/− and TNFR1−/−/R2−/− mice and found that both receptors are necessary for maximal induction of ABCA1 by TNF. Peritoneal macrophages from TNFR1−/−/R2−/− mice had no change in ABCA1 mRNA levels when treated with TNF while cells from TNFR2−/− mice had ABCA1 mRNA levels that were half that of wild-type (WT) cells. In contrast, incubating TNFR1−/−/R2−/− mice with LT increased ABCA1 by stabilizing the protein, which was not observed in WT mice and this was associated with downstream signaling through the LTβ receptor.


      TNF requires both of its receptors to maximally induce ABCA1. Despite previous studies suggesting that LT has proatherogenic properties, we found that LT increases ABCA1 protein in TNFR1−/−/R2−/− but not WT macrophages and may supplement TNF in enhancing ABCA1-dependent cholesterol export from early atherosclerotic lesions.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Lloyd-Jones D.
        • Adams R.
        • Carnethon M.
        • et al.
        Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
        Circulation. 2009; 119: 480-486
        • Boesten L.S.
        • Zadelaar A.S.
        • van Nieuwkoop A.
        • et al.
        Tumor necrosis factor-alpha promotes atherosclerotic lesion progression in APOE*3-Leiden transgenic mice.
        Cardiovasc Res. 2005; 66: 179-185
        • Schreyer S.A.
        • Peschon J.J.
        • LeBoeuf R.C.
        Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55.
        J Biol Chem. 1996; 271: 26174-26178
        • Schreyer S.A.
        • Vick C.M.
        • LeBoeuf R.C.
        Loss of lymphotoxin-alpha but not tumor necrosis factor-alpha reduces atherosclerosis in mice.
        J Biol Chem. 2002; 277: 12364-12368
        • Aggarwal B.B.
        Signalling pathways of the TNF superfamily: a double-edged sword.
        Nat Rev Immunol. 2003; 3: 745-756
        • Oram J.F.
        HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol.
        Arterioscler Thromb Vasc Biol. 2003; 23: 720-727
        • Oram J.F.
        • Heinecke J.W.
        ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease.
        Physiol Rev. 2005; 85: 1343-1372
        • Assmann G.
        • von Eckardstein A.
        • Brewer H.B.J.
        Familial high density lipoprotein deficiency: tangier disease.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York1995
        • Clee S.M.
        • Kastelein J.J.
        • van Dam M.
        • et al.
        Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.
        J Clin Invest. 2000; 106: 1263-1270
        • Serfaty-Lacrosniere C.
        • Civeira F.
        • Lanzberg A.
        • et al.
        Homozygous Tangier disease and cardiovascular disease.
        Atherosclerosis. 1994; 107: 85-98
        • Ware C.F.
        Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways.
        Immunol Rev. 2008; 223: 186-201
        • Gerbod-Giannone M.C.
        • Li Y.
        • Holleboom A.
        • et al.
        TNFalpha induces ABCA1 through NF-kappaB in macrophages and in phagocytes ingesting apoptotic cells.
        Proc Natl Acad Sci U S A. 2006; 103: 3112-3117
        • Wang Y.
        • Oram J.F.
        Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1.
        J Biol Chem. 2002; 277: 5692-5697
        • Wang Y.
        • Oram J.F.
        Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway.
        J Lipid Res. 2007; 48: 1062-1068
        • Goldstein J.L.
        • Ho Y.K.
        • Basu S.K.
        • Brown M.S.
        Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition.
        Proc Natl Acad Sci U S A. 1979; 76: 333-337
        • Mendez A.J.
        • Oram J.F.
        • Bierman E.L.
        Protein kinase C as a mediator of high density lipoprotein receptor-dependent efflux of intracellular cholesterol.
        J Biol Chem. 1991; 266: 10104-10111
        • Oram J.F.
        • Mendez A.J.
        • Slotte J.P.
        • Johnson T.F.
        High density lipoprotein apolipoproteins mediate removal of sterol from intracellular pools but not from plasma membranes of cholesterol-loaded fibroblasts.
        Arterioscler Thromb. 1991; 11: 403-414
        • Wellington C.L.
        • Walker E.K.
        • Suarez A.
        • et al.
        ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation.
        Lab Invest. 2002; 82: 273-283
        • Androlewicz M.J.
        • Browning J.L.
        • Ware C.F.
        Lymphotoxin is expressed as a heteromeric complex with a distinct 33-kDa glycoprotein on the surface of an activated human T cell hybridoma.
        J Biol Chem. 1992; 267: 2542-2547
        • Browning J.L.
        • Androlewicz M.J.
        • Ware C.F.
        Lymphotoxin and an associated 33-kDa glycoprotein are expressed on the surface of an activated human T cell hybridoma.
        J Immunol. 1991; 147: 1230-1237
        • Browning J.L.
        • Ngam-ek A.
        • Lawton P.
        • et al.
        Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface.
        Cell. 1993; 72: 847-856
        • McCarthy D.D.
        • Summers-Deluca L.
        • Vu F.
        • Chiu S.
        • Gao Y.
        • Gommerman J.L.
        The lymphotoxin pathway: beyond lymph node development.
        Immunol Res. 2006; 35: 41-54
        • Lo J.C.
        • Basak S.
        • James E.S.
        • et al.
        Coordination between NF-kappaB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues.
        Blood. 2006; 107: 1048-1055
        • Schneider K.
        • Potter K.G.
        • Ware C.F.
        Lymphotoxin and LIGHT signaling pathways and target genes.
        Immunol Rev. 2004; 202: 49-66
        • Aiello R.J.
        • Brees D.
        • Francone O.L.
        ABCA1-deficient mice: insights into the role of monocyte lipid efflux in HDL formation and inflammation.
        Arterioscler Thromb Vasc Biol. 2003; 23: 972-980
        • van Eck M.
        • Bos I.S.
        • Kaminski W.E.
        • et al.
        Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues.
        Proc Natl Acad Sci U S A. 2002; 99: 6298-6303
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        • Jensen G.B.
        • Steffensen R.
        • Tybjaerg-Hansen A.
        Genetic variation in ABCA1 predicts ischemic heart disease in the general population.
        Arterioscler Thromb Vasc Biol. 2008; 28: 180-186
        • Singaraja R.R.
        • Fievet C.
        • Castro G.
        • et al.
        Increased ABCA1 activity protects against atherosclerosis.
        J Clin Invest. 2002; 110: 35-42
        • Schottelius A.J.
        • Moldawer L.L.
        • Dinarello C.A.
        • Asadullah K.
        • Sterry W.
        • Edwards 3rd., C.K.
        Biology of tumor necrosis factor-alpha-implications for psoriasis.
        Exp Dermatol. 2004; 13: 193-222
        • Turner N.A.
        • Mughal R.S.
        • Warburton P.
        • O’Regan D.J.
        • Ball S.G.
        • Porter K.E.
        Mechanism of TNFalpha-induced IL-1alpha. IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones.
        Cardiovasc Res. 2007; 76: 81-90
        • Tartaglia L.A.
        • Pennica D.
        • Goeddel D.V.
        Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor.
        J Biol Chem. 1993; 268: 18542-18548
        • Monden Y.
        • Kubota T.
        • Inoue T.
        • et al.
        Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction.
        Am J Physiol Heart Circ Physiol. 2007; 293: H743-753
        • Ramani R.
        • Mathier M.
        • Wang P.
        • et al.
        Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling.
        Am J Physiol Heart Circ Physiol. 2004; 287: H1369-1377
        • Fujita M.
        • Ikegame S.
        • Harada E.
        • et al.
        TNF receptor 1 and 2 contribute in different ways to resistance to Legionella pneumophila-induced mortality in mice.
        Cytokine. 2008; 44: 298-303
        • Sedger L.M.
        • Hou S.
        • Osvath S.R.
        • et al.
        Bone marrow B cell apoptosis during in vivo influenza virus infection requires TNF-alpha and lymphotoxin-alpha.
        J Immunol. 2002; 169: 6193-6201
        • Togbe D.
        • de Sousa P.L.
        • Fauconnier M.
        • et al.
        Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.
        PLoS ONE. 2008; 3: e2608
        • Kavurma M.M.
        • Tan N.Y.
        • Bennett M.R.
        Death receptors and their ligands in atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2008; 28: 1694-1702
        • Lee N.K.
        • Lee S.Y.
        Modulation of life and death by the tumor necrosis factor receptor-associated factors (TRAFs).
        J Biochem Mol Biol. 2002; 35: 61-66
        • Derudder E.
        • Dejardin E.
        • Pritchard L.L.
        • Green D.R.
        • Korner M.
        • Baud V.
        RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100.
        J Biol Chem. 2003; 278: 23278-23284
        • Lu R.
        • Arakawa R.
        • Ito-Osumi C.
        • Iwamoto N.
        • Yokoyama S.
        ApoA-I facilitates ABCA1 recycle/accumulation to cell surface by inhibiting its intracellular degradation and increases HDL generation.
        Arterioscler Thromb Vasc Biol. 2008; 28: 1820-1824
        • Singaraja R.R.
        • Kang M.H.
        • Vaid K.
        • et al.
        Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function.
        Circ Res. 2009; 105: 138-147
        • Tang C.
        • Oram J.F.
        The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes.
        Biochim Biophys Acta. 2009; 1791: 563-572
        • Wang N.
        • Chen W.
        • Linsel-Nitschke P.
        • et al.
        A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I.
        J Clin Invest. 2003; 111: 99-107
        • Chaturvedi M.M.
        • LaPushin R.
        • Aggarwal B.B.
        Tumor necrosis factor and lymphotoxin. Qualitative and quantitative differences in the mediation of early and late cellular response.
        J Biol Chem. 1994; 269: 14575-14583