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Exclusive expression of transmembrane TNF-α in mice reduces the inflammatory response in early lipid lesions of aortic sinus

      Abstract

      We investigated the effect of transmembrane form of tumor necrosis factor-alpha (TNF) on atherosclerosis in mice. We compared the development of early atherosclerotic lesions in the aortic sinus of (1) TNF-deficient mice that express only a non-cleavable transmembrane form of TNF (tmTNF), (2) wild-type (WT) C57BL/6 mice, and (3) TNF-deficient mice (TNF−/−). All mice were fed an atherogenic diet for 20 weeks. Lipid deposition was the most prominent in WT mice (25030±5693 μm2), tended to be lower in tmTNF mice (13640±2190 μm2, P>0.05 versus WT mice) and rare in TNF−/− mice (1408±513 μm2, P<0.05 versus tmTNF and P<0.01 versus WT). Macrophage accumulation was five-fold lower (P<0.01) in tmTNF than in WT mice. In addition, the α-actin immuno-reactivity of medial smooth muscle cells remained intact in tmTNF mice but not in WT mice. In WT mice, the plasma lipid profile was significantly more atherogenic than that of TNF−/− mice (P<0.05), but not significantly different from that of tmTNF mice (P>0.05). These results indicated that in contrast to TNF−/− mice, mice expressing exclusively tmTNF were not completely protected from early atherosclerotic lesion formation, although their lesions have a less inflammatory state than those of WT mice, which underlines the stronger proinflammatory potential of soluble TNF.

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      References

        • Barath P.
        • Fishbein M.C.
        • Cao J.
        • Berenson J.
        • Helfant R.H.
        • Forrester J.S.
        Detection and localization of tumor necrosis factor in human atheroma.
        Am. J. Cardiol. 1990; 65: 297-302
        • Tipping P.G.
        • Hancock W.W.
        Production of tumor necrosis factor and interleukin-1 by macrophages from human atheromatous plaques.
        Am. J. Pathol. 1993; 142: 1721-1728
        • Ridker P.M.
        • Rifai N.
        • Pfeffer M.
        • Sacks F.
        • Lepage S.
        • Braunwald E.
        Elevation of tumor necrosis factor-{alpha} and increased risk of recurrent coronary events after myocardial infarction.
        Circulation. 2000; 101: 2149-2153
        • Skoog T.
        • Dichtl W.
        • Boquist S.
        • Skoglund-Andersson C.
        • Karpe F.
        • Tang R.
        • et al.
        Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle-aged men.
        Eur. Heart J. 2002; 23: 376-383
        • Jovinge S.
        • Hamsten A.
        • Tornvall P.
        • Proudler A.
        • Bavenholm P.
        • Ericsson C.G.
        • et al.
        Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease.
        Metabolism. 1998; 47: 113-118
        • Bruunsgaard H.
        • Skinhoj P.
        • Pedersen A.N.
        • Schroll M.
        • Pedersen B.K.
        Ageing, tumour necrosis factor-alpha (TNF-alpha) and atherosclerosis.
        Clin. Exp. Immunol. 2000; 121: 255-260
        • Libby P.
        • Sukhova G.
        • Lee R.T.
        • Galis G.Z.
        Cytokines regulate vascular functions related to stability of the atherosclerotic plaque.
        J. Cardiovasc. Pharmacol. 1995; 25: S9-S12
        • Elhage R.
        • Maret A.
        • Pieraggi M.-T.
        • Thiers J.C.
        • Arnal J.F.
        • Bayard F.
        Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice.
        Circulation. 1998; 97: 242-244
        • Niemann-Jonsson A.
        • Dimayuga P.
        • Jovinge S.
        • Calara F.
        • Ares M.P.
        • Fredrikson G.N.
        • et al.
        Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2205-2211
        • Li A.C.
        • Brown K.K.
        • Silvestre M.J.
        • Willson T.M.
        • Palinski W.
        • Glass C.K.
        Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.
        J. Clin. Invest. 2000; 106: 523-531
        • Von Der Thusen J.H.
        • Kuiper J.
        • Fekkes M.L.
        • De Vos P.
        • Van Berkel T.J.
        • Biessen E.A.
        Attenuation of atherogenesis by systemic and local adenovirus-mediated gene transfer of interleukin-10 in LDLr−/− mice.
        FASEB J. 2001; 15: 2730-2732
        • Zhou Z.
        • Lauer M.A.
        • Wang K.
        • Forudi F.
        • Zhou X.
        • Song X.
        • et al.
        Effect of anti-tumor necrosis factor-alpha polyclonal antibody on restenosis after balloon angioplasty in a rabbit atherosclerotic model.
        Atherosclerosis. 2002; 161: 153-159
        • Reckless J.
        • Rubin E.M.
        • Verstuyft J.B.
        • Metcalfe J.C.
        • Grainger D.J.
        Monocyte chemoattractant protein-1 but not tumor necrosis factor-{alpha} is correlated with monocyte infiltration in mouse lipid lesions.
        Circulation. 1999; 99: 2310-2316
        • Hansen P.R.
        • Chew M.
        • Zhou J.
        • Daugherty A.
        • Heegaard N.
        • Jensen P.
        • et al.
        Freunds adjuvant alone is antiatherogenic in apoE-deficient mice and specific immunization against TNFalpha confers no additional benefit.
        Atherosclerosis. 2001; 158: 87-94
        • 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
        • Black R.A.
        • Rauch C.T.
        • Kozlosky C.J.
        • Peschon J.J.
        • Slack J.L.
        • Wolfson M.F.
        • et al.
        A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.
        Nature. 1997; 385: 729-733
        • Moss M.L.
        • Jin S.L.
        • Milla M.E.
        • Bickett D.M.
        • Burkhart W.
        • Carter H.L.
        • et al.
        Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.
        Nature. 1997; 385: 733-736
        • Kriegler M.
        • Perez C.
        • DeFay K.
        • Albert I.
        • Lu S.D.
        A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF.
        Cell. 1988; 53: 45-53
        • Haas E.
        • Grell M.
        • Wajant H.
        • Scheurich P.
        Continuous autotropic signaling by membrane-expressed tumor necrosis factor.
        J. Biol. Chem. 1999; 274: 18107-18112
        • Clauss M.
        • Sunderkotter C.
        • Sveinbjornsson B.
        • Hippenstiel S.
        • Willuweit A.
        • Marino M.
        • et al.
        A permissive role for tumor necrosis factor in vascular endothelial growth factor-induced vascular permeability.
        Blood. 2001; 97: 1321-1329
        • Mueller C.
        • Corazza N.
        • Trachsel-Loseth S.
        • Eugster H.-P.
        • Buhler-Jungo M.
        • Brunner T.
        • et al.
        Noncleavable transmembrane mouse tumor necrosis factor-alpha (TNFalpha) mediates effects distinct from those of wild-type TNFalpha in vitro and in vivo.
        J. Biol. Chem. 1999; 274: 38112-38118
        • Ruuls S.R.
        • Hoek R.M.
        • Ngo V.N.
        • McNeil T.
        • Lucian L.A.
        • Janatpour M.J.
        • et al.
        Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation.
        Immunity. 2001; 15: 533-543
        • Olleros M.L.
        • Guler R.
        • Corazza N.
        • Vesin D.
        • Eugster H.-P.
        • Marchal G.
        • et al.
        Transmembrane TNF induces an efficient cell-mediated immunity and resistance to mycobacterium bovis Bacillus Calmette-Guerin infection in the absence of secreted TNF and lymphotoxin-{alpha}.
        J. Immunol. 2002; 168: 3394-3401
        • Libby P.
        • Ridker P.M.
        • Maseri A.
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Steinberg D.
        Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.
        Nat. Med. 2002; 8: 1211-1217
        • Eugster H.P.
        • Muller M.
        • Karrer U.
        • Car B.D.
        • Schnyder B.
        • Eng V.M.
        • et al.
        Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha double-deficient mice.
        Int. Immunol. 1996; 8 ([abs.html]): 23-36
        • Mallat Z.
        • Besnard S.
        • Duriez M.
        • Deleuze V.
        • Emmanuel F.
        • Bureau M.F.
        • et al.
        Protective role of interleukin-10 in atherosclerosis.
        Circ. Res. 1999; 85: e17-e24
        • Boisfer E.
        • Lambert G.
        • Atger V.
        • Tran N.Q.
        • Pastier D.
        • Benetollo C.
        • et al.
        Overexpression of human apolipoprotein A-II in mice induces hypertriglyceridemia due to defective very low density lipoprotein hydrolysis.
        J. Biol. Chem. 1999; 274: 11564-11572
        • Declerck P.J.
        • Verstreken M.
        • Collen D.
        Immunoassay of murine t-PA, u-PA and PAI-1 using monoclonal antibodies raised in gene-inactivated mice.
        Thromb. Haemost. 1995; 74: 1305-1309
        • Paigen B.
        • Morrow A.
        • Holmes P.A.
        • Mitchell D.
        • Williams R.A.
        Quantitative assessment of atherosclerotic lesions in mice.
        Atherosclerosis. 1987; 68: 231-240
        • Morange P.E.
        • Lijnen H.R.
        • Alessi M.C.
        • Kopp F.
        • Collen D.
        • Juhan-Vague I.
        Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1150-1154
        • Kim C.J.
        • Khoo J.C.
        • Gillotte-Taylor K.
        • Li A.
        • Palinski W.
        • Glass C.K.
        • et al.
        Polymerase chain reaction-based method for quantifying recruitment of monocytes to mouse atherosclerotic lesions in vivo: enhancement by tumor necrosis factor-alpha and interleukin-1 beta.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1976-1982
        • Haraldsen G.
        • Kvale D.
        • Lien B.
        • Farstad I.N.
        • Brandtzaeg P.
        Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells.
        J. Immunol. 1996; 156: 2558-2565
        • Sica A.
        • Wang J.M.
        • Colotta F.
        • Dejana E.
        • Mantovani A.
        • Oppenheim J.J.
        • et al.
        Monocyte chemotactic and activating factor gene expression induced in endothelial cells by IL-1 and tumor necrosis factor.
        J. Immunol. 1990; 144: 3034-3038
        • Hsu H.Y.
        • Twu Y.C.
        Tumor necrosis factor-alpha-mediated protein kinases in regulation of scavenger receptor and foam cell formation on macrophage.
        J. Biol. Chem. 2000; 275: 41035-41048
        • Regan C.P.
        • Adam P.J.
        • Madsen C.S.
        • Owens G.K.
        Molecular mechanisms of decreased smooth muscle differentiation marker expression after vascular injury.
        J. Clin. Invest. 2000; 106: 1139-1147
        • Beyaert R.
        • Cuenda A.
        • Vanden Berghe W.
        • Plaisance S.
        • Lee J.C.
        • Haegeman G.
        • et al.
        The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor.
        EMBO J. 1996; 15: 1914-1923
        • van Hinsbergh V.W.
        • Bauer K.A.
        • Kooistra T.
        • Kluft C.
        • Dooijewaard G.
        • Sherman M.L.
        • et al.
        Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products.
        Blood. 1990; 76: 2284-2289
        • Plump A.S.
        • Scott C.J.
        • Breslow J.L.
        Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse.
        Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 9607-9611
        • Rutledge J.C.
        • Mullick A.E.
        • Gardner G.
        • Goldberg I.J.
        Direct visualization of lipid deposition and reverse lipid transport in a perfused artery: roles of VLDL and HDL.
        Circ. Res. 2000; 86: 768-773
        • Song H.
        • Saito K.
        • Fujigaki S.
        • Noma A.
        • Ishiguro H.
        • Nagatsu T.
        • et al.
        IL-1 beta and TNF-alpha suppress apolipoprotein (apo) E secretion and apo A-I expression in HepG2 cells.
        Cytokine. 1998; 10: 275-280
        • Smith J.D.
        • Trogan E.
        • Ginsberg M.
        • Grigaux C.
        • Tian J.
        • Miyata M.
        Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E.
        Proc. Natl. Acad. Sci. U.S.A. 1995; 92: 8264-8268
        • Tangirala R.K.
        • Rubin E.M.
        • Palinski W.
        Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice.
        J. Lipid Res. 1995; 36: 2320-2328
        • Yoshida H.
        • Hasty A.H.
        • Major A.S.
        • Ishiguro H.
        • Su Y.R.
        • Gleaves L.A.
        • et al.
        Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice.
        Circulation. 2001; 104: 2820-2825