title: RAGE-dependent regulation of calcium-binding proteins S100A8 and S100A9 in human THP-1.
abstract: Proinflammatory cell activation via the receptor for advanced glycation end products (RAGE) pathway may play a central pathogenetic role in atherosclerosis. Since S100A8/A9 was recently identified as ligand of RAGE, we determined the effects of proinflammatory cytokines on RAGE-mediated induction of gene expression of S100A8 and S100A9. mRNA levels of S100A8 and S100A9 were upregulated following cytokine stimulation with IL-6 (1, 10, 100 ng/ml) or TNFα (10 ng/ml) in human THP-1 cells. Preincubation of cells with 2000 ng/ml AGE (advanced glycation end products) before cytokine stimulation resulted in upregulation of RAGE. Pretreatment of THP-1 with AGE followed by stimulation with IL-6 (10 ng/ml) or TNFα (10 ng/ml) further increased S100A8 and S100A9 mRNA expression and S100A8/A9 release into cell culture supernatant, as compared to pretreatment with non-glycated albumin as control. Binding of AGE to RAGE was blocked with a neutralizing anti-RAGE antibody. Normal mouse IgG served as control. Cytokine-stimulated induction of S100A8 and S100A9 mRNA levels as well as of S100A8/A9 release after preincubation of cells with AGE were significantly suppressed by RAGE blockade, indicating a RAGE-dependent pathway of AGE-mediated S100A8/A9 expression.The cytokine-induced potentiated S100A8 and S100A9 expression under conditions with a high AGE burden is able to aggravate proinflammatory conditions via activation of the RAGE pathway.
authors.affiliation: Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie, Charité - Universitätsmedizin Berlin, Campus Mitte, Germany. kai.eggers@charite.de
authors.forename: K
authors.initials: K
authors.lastname: Eggers
authors.forename: K
authors.initials: K
authors.lastname: Sikora
authors.forename: M
authors.initials: M
authors.lastname: Lorenz
authors.forename: T
authors.initials: T
authors.lastname: Taubert
authors.forename: M
authors.initials: M
authors.lastname: Moobed
authors.forename: G
authors.initials: G
authors.lastname: Baumann
authors.forename: K
authors.initials: K
authors.lastname: Stangl
authors.forename: V
authors.initials: V
authors.lastname: Stangl
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha