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(American Journal of Pathology. 2006;169:1223-1237.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050713

Posttranslationally Modified Proteins as Mediators of Sustained Intestinal Inflammation

Martin Andrassy*, John Igwe*, Frank Autschbach{dagger}, Christian Volz*, Andrew Remppis*, Markus F. Neurath{ddagger}, Erwin Schleicher§, Per M. Humpert*, Thoralf Wendt*, Birgit Liliensiek*, Michael Morcos*, Stephan Schiekofer*, Kirsten Thiele*, Jiang Chen*, Rose Kientsch-Engel, Ann-Marie Schmidt||, Wolfgang Stremmel*, David M. Stern**, Hugo A. Katus*, Peter P. Nawroth* and Angelika Bierhaus*

From the Department of Medicine I, III, and IV,* and the Institute of Pathology,{dagger} University of Heidelberg, Heidelberg, Germany; the Laboratory of Immunology I,{ddagger} Medical Clinic, University of Mainz, Mainz, Germany; the Department of Medicine IV,§ University Tübingen, Tübingen, Germany; Roche Diagnostics GmbH, Penzberg, Germany; the College of Physicians and Surgeons,|| Columbia University, New York, New York; and the Deans’s Office,** College of Medicine, University of Cincinnati, Cincinnati, Ohio

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)-{kappa}B-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-{kappa}B 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-{kappa}B activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-{kappa}B activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-{kappa}B 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-{kappa}B activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE–/– mice. A comparable up-regulation of NF-{kappa}B 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.




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