title: Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells.
abstract: Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to diverse reducing sugars. Accumulation of AGEs induces diabetes complications. Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications. Activation of monocytes/macrophages and T cells plays roles in the pathogenesis of atherosclerosis. The activation of T cells requires the enhanced expression of adhesion molecules on monocytes. AGEs activate monocytes by engaging the receptor for AGE (RAGE); however, little is known about the profile of agonist activity of diverse AGE moieties on monocytes. We investigated the effect of four distinct AGE subtypes (AGE-modified bovine serum albumin; AGE-2, AGE-3, AGE-4, and AGE-5) at concentrations ranging from 0.1 to 100 microg/ml on the expression of intercellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes and its impact on the production of interferon-gamma and tumor necrosis factor-alpha in human peripheral blood mononuclear cells. Among the AGEs examined, AGE-2 and AGE-3 selectively induced adhesion molecule expression and cytokine production. Antagonism experiments using antibodies against adhesion molecules demonstrated that cell-to-cell interaction between monocytes and T/natural killer cells was involved in AGE-2- and AGE-3-induced cytokine production. AGE-2 and AGE-3 up-regulated the expression of RAGE on monocytes. The effects of AGE-2 and AGE-3 were inhibited by nuclear factor-kappaB and p38 mitogen-activated protein kinase inhibitors. These results indicated that AGE-2 and AGE-3 activated monocytes via RAGE, leading to the up-regulation of adhesion molecule expression and cytokine production.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Hideo Kohka
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Ohashi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D015815:Cell Adhesion Molecules; D016207:Cytokines; D017127:Glycation End Products, Advanced; D060945:Inducible T-Cell Co-Stimulator Ligand; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018799:Intercellular Adhesion Molecule-1