title: Chylomicron remnants upregulate CD40 expression via the ERK pathway and a redox-sensitive mechanism in THP-1 cells.
abstract: CD40 is a 48kDa 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.
authors.affiliation: Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kamemura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takaishi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takahashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D053298:Chylomicron Remnants / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D053298:Chylomicron Remnants; D017382:Reactive Oxygen Species; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases