title: Advanced glycosylation end products induce NF-kappaB dependent iNOS expression in RAW 264.7 cells.
abstract: Advanced glycosylation end products (AGEs) have been implicated in the pathogenesis of diabetic complications. Treatment of RAW 264.7 macrophages with bovine serum albumin (BSA)-derived AGEs caused dose- and time-dependent increases in nitrite production and inducible nitric oxide synthase (iNOS) expression. These effects were blocked by the nuclear factor-kappa B (NF-kappaB) inhibitor, pyrrolidone dithiocarbamate (PDTC). BSA-AGEs also stimulated the translocation of p65 NF-kappaB from cytosol to the nucleus. Electrophoretic mobility shift assay revealed that the NF-kappaB DNA-protein-binding activity was enhanced by AGEs. The tyrosine kinase inhibitor, genistein, the phosphatidylinositol-3-kinase (PI 3-K) inhibitor, LY 294002, the protein kinase C (PKC) inhibitor, Ro 31-8220, and the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 203580, all inhibited AGEs-stimulated iNOS expression, NO release, NF-kappaB translocation and NF-kappaB DNA binding activity. These results suggest that AGEs may activate NF-kappaB via an upstream signaling cascade composed of tyrosine kinase, PI 3-K, PKC, and p38 MAPK, resulting in the induction of iNOS expression in RAW 264.7 macrophages.
authors.affiliation: School of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Chao-Ming
authors.initials: CM
authors.lastname: Huang
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Lin
authors.forename: Yuan-Sun
authors.initials: YS
authors.lastname: Ho
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Chen
authors.forename: Horng-Mo
authors.initials: HM
authors.lastname: Lee
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002457:Cell Extracts; D002460:Cell Line; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000187:drug effects / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000906:Antibodies; D002457:Cell Extracts; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse