Advertisement

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

      Abstract

      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.

      Keywords

      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:

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

      References

        • 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