Posttranslationally modified proteins as mediators of sustained intestinal inflammation

Am J Pathol. 2006 Oct;169(4):1223-37. doi: 10.2353/ajpath.2006.050713.


Oxidative and carbonyl stress leads to generation of N(epsilon)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-kappaB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-kappaB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-kappaB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-kappaB activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-kappaB activation, lasting 5 days, was primarily inhibited by either depletion of CML-mps or by the addition of sRAGE, p44/42 and p38 MAPKinase-specific inhibitors. Consistently, CML-mps isolated from inflamed gut areas and rectally applied into mice caused NF-kappaB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE-/- mice. A comparable up-regulation of NF-kappaB and inflammation on rectal application of CML-mps was observed in IL-10-/- mice. Thus, CML-mps generated in inflammatory lesions have the capacity to elicit a RAGE-dependent intestinal inflammatory response.

MeSH terms

  • Adult
  • Animals
  • Calgranulin A / analysis
  • Calgranulin A / metabolism*
  • Calgranulin B / analysis
  • Calgranulin B / metabolism*
  • Cell Extracts / chemistry
  • Cell Extracts / pharmacology
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Female
  • Humans
  • Inflammatory Bowel Diseases / metabolism*
  • Inflammatory Bowel Diseases / pathology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / pathology
  • Lysine / analogs & derivatives*
  • Lysine / analysis
  • Lysine / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • NF-kappa B / agonists
  • NF-kappa B / metabolism
  • Protein Kinase Inhibitors
  • Protein Processing, Post-Translational*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors


  • Calgranulin A
  • Calgranulin B
  • Cell Extracts
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • N(6)-carboxymethyllysine
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Lysine