Chylomicron remnants upregulate CD40 expression via the ERK pathway and a redox-sensitive mechanism in THP-1 cells


      CD40 is a 48 kDa phosphorylated transmembrane glycoprotein that belongs to the tumor necrosis factor receptor superfamily and may play a role in formation of atherosclerotic plaques. Here, we investigated the effect of chylomicron remnants on CD40 expression in the human premonocytic cell line, THP-1 cells. Chylomicron remnants upregulated the expression of CD40 protein and mRNA in a dose- and time-dependent manner. Further, chylomicron remnants increased the generation of reactive oxygen species as determined by an increasing level of 2′,7′-dichlorofluorescein. Pretreatment with the antioxidant, N-acetylcysteine, inhibited chylomicron remnant-induced CD40 protein expression by 60%. On the other hand, chylomicron remnants transiently increased the phosphorylation of extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen-activated protein kinase (MAPK). Pretreatment with the MAPK kinase inhibitor, U0126, completely inhibited chylomicron remnants-induced CD40 protein expression, whereas the p38 MAPK inhibitor, SB203580, had no effect. Pretreatment with N-acetylcysteine had no effect on chylomicron remnant-induced ERK 1/2 phosphorylation. These data suggest that CD40 expression stimulated by chylomicron remnants in THP-1 cells is dependent on ERK 1/2-mediated pathway, which is followed by redox-sensitive mechanism-dependent and independent pathway. Thus, chylomicron remnants may contribute to the formation of atherosclerotic plaques via their immunological and proinflammatory effects.


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        • Phillips N.R.
        • Waters D.
        • Havel R.J.
        Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events.
        Circulation. 1993; 88: 2762-2770
        • Hodis H.N.
        • Mack W.J.
        • Azen S.P.
        • et al.
        Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.
        Circulation. 1994; 90: 42-49
        • Patsch J.R.
        • Miesenbock G.
        • Hopferwieser T.
        • et al.
        Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state.
        Arterioscler Thromb. 1992; 12: 1336-1345
        • Kugiyama K.
        • Doi H.
        • Takazoe K.
        • et al.
        Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease.
        Circulation. 1999; 99: 2858-2860
        • Fujioka Y.
        • Cooper A.D.
        • Fong L.G.
        Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages.
        J Lipid Res. 1998; 39: 2339-2349
        • Kawasaki S.
        • Taniguchi T.
        • Fujioka Y.
        • et al.
        Chylomicron remnant induces apoptosis in vascular endothelial cells.
        Ann N Y Acad Sci. 2000; 902: 336-341
        • Morimoto S.
        • Fujioka Y.
        • Hosoai H.
        • et al.
        The renin-angiotensin system is involved in the production of plasminogen activator inhibitor type 1 by cultured endothelial cells in response to chylomicron remnants.
        Hypertens Res. 2003; 26: 315-323
        • Domoto K.
        • Taniguchi T.
        • Takaishi H.
        • et al.
        Chylomicron remnants induce monocyte chemoattractant protein-1 expression via p38 MAPK activation in vascular smooth muscle cells.
        Atherosclerosis. 2003; 171: 193-200
        • Takahashi Y.
        • Fujioka Y.
        • Takahashi T.
        • et al.
        Chylomicron remnants regulate early growth response factor-1 in vascular smooth muscle cells.
        Life Sci. 2005; 77: 670-682
        • Kehry M.R.
        CD40-mediated signaling in B cells. Balancing cell survival, growth, and death.
        J Immunol. 1996; 156: 2345-2348
        • Mach F.
        • Schonbeck U.
        • Sukhova G.K.
        • et al.
        Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis.
        Proc Natl Acad Sci USA. 1997; 94: 1931-1936
        • Schonbeck U.
        • Libby P.
        CD40 signaling and plaque instability.
        Circ Res. 2001; 89: 1092-10103
        • Mach F.
        • Schonbeck U.
        • Sukhova G.K.
        • Atkinson E.
        • Libby P.
        Reduction of atherosclerosis in mice by inhibition of CD40 signalling.
        Nature. 1998; 394: 200-203
        • Boulton T.G.
        • Nye S.H.
        • Robbins D.J.
        • et al.
        ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
        Cell. 1991; 65: 663-675
        • Seger R.
        • Krebs E.G.
        The MAPK signaling cascade.
        FASEB J. 1995; 9: 726-735
        • Burysek L.
        • Syrovets T.
        • Simmet T.
        The serine protease plasmin triggers expression of MCP-1 and CD40 in human primary monocytes via activation of p38 MAPK and janus kinase (JAK)/STAT signaling pathways.
        J Biol Chem. 2002; 277: 33509-33517
        • Arrighi J.F.
        • Rebsamen M.
        • Rousset F.
        • Kindler V.
        • Hauser C.
        A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers.
        J Immunol. 2001; 166: 3837-3845
        • Griendling K.K.
        • FitzGerald G.A.
        Oxidative stress and cardiovascular injury. Part II. Animal and human studies.
        Circulation. 2003; 108: 2034-2040
        • Guyton K.Z.
        • Liu Y.
        • Gorospe M.
        • Xu Q.
        • Holbrook N.J.
        Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury.
        J Biol Chem. 1996; 271: 4138-4142
        • Ogura M.
        • Kitamura M.
        Oxidant stress incites spreading of macrophages via extracellular signal-regulated kinases and p38 mitogen-activated protein kinase.
        J Immunol. 1998; 161: 3569-3574
        • Basu S.K.
        • Goldstein J.L.
        • Anderson G.W.
        • Brown M.S.
        Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts.
        Proc Natl Acad Sci USA. 1976; 73: 3178-3182
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measure with the Folin phenol reagent.
        J Bio Chem. 1951; 193: 265-275
        • Li D.
        • Liu L.
        • Chen H.
        • Sawamura T.
        • Mehta J.L.
        LOX-1, an oxidized LDL endothelial receptor, induces CD40/CD40L signaling in human coronary artery endothelial cells.
        Arterioscler Thromb Vasc Biol. 2003; 23: 816-821
        • Schonbeck U.
        • Gerdes N.
        • Varo N.
        • et al.
        Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells.
        Circulation. 2002; 106: 2888-2893
        • Kahler J.
        • Ewert A.
        • Weckmuller J.
        • et al.
        Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells.
        J Cardiovasc Pharmacol. 2001; 38: 49-57
        • Griendling K.K.
        • Sorescu D.
        • Lassegue B.
        • Ushio-Fukai M.
        Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2175-2183
        • Meilhac O.
        • Zhou M.
        • Santanam N.
        • Parthasarathy S.
        Lipid peroxides induce expression of catalase in cultured vascular cells.
        J Lipid Res. 2000; 41: 1205-1213
        • Doi H.
        • Kugiyama K.
        • Oka H.
        • et al.
        Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism.
        Circulation. 2000; 102: 670-676
        • Shin H.K.
        • Kim Y.K.
        • Kim K.Y.
        • Lee J.H.
        • Hong K.W.
        Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein receptor-1 activation: prevention by cilostazol.
        Circulation. 2004; 109: 1022-1028
        • Yu K.C.
        • Mamo J.C.
        Chylomicron-remnant-induced foam cell formation and cytotoxicity: a possible mechanism of cell death in atherosclerosis.
        Clin Sci (Lond). 2000; 98: 183-192
        • Rutault K.
        • Alderman C.
        • Chain B.M.
        • Katz D.R.
        Reactive oxygen species activate human peripheral blood dendritic cells.
        Free Radic Biol Med. 1999; 26: 232-238