Advanced glycosylation end products induce NF-kappaB dependent iNOS expression in RAW 264.7 cells

Mol Cell Endocrinol. 2002 Aug 30;194(1-2):9-17. doi: 10.1016/s0303-7207(02)00212-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Antibodies / pharmacology
  • Cell Extracts
  • Cell Line
  • Glycation End Products, Advanced / pharmacology*
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / biosynthesis*
  • Nitric Oxide Synthase / drug effects
  • Nitric Oxide Synthase / immunology
  • Nitric Oxide Synthase Type II
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects


  • Antibodies
  • Cell Extracts
  • Glycation End Products, Advanced
  • NF-kappa B
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse