title: Posttranslationally modified proteins as mediators of sustained intestinal inflammation.
abstract: 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.
authors.affiliation: Department of Medicine I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Andrassy
authors.forename: John
authors.initials: J
authors.lastname: Igwe
authors.forename: Frank
authors.initials: F
authors.lastname: Autschbach
authors.forename: Christian
authors.initials: C
authors.lastname: Volz
authors.forename: Andrew
authors.initials: A
authors.lastname: Remppis
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.forename: Per M
authors.initials: PM
authors.lastname: Humpert
authors.forename: Thoralf
authors.initials: T
authors.lastname: Wendt
authors.forename: Birgit
authors.initials: B
authors.lastname: Liliensiek
authors.forename: Michael
authors.initials: M
authors.lastname: Morcos
authors.forename: Stephan
authors.initials: S
authors.lastname: Schiekofer
authors.forename: Kirsten
authors.initials: K
authors.lastname: Thiele
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.forename: Rose
authors.initials: R
authors.lastname: Kientsch-Engel
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
mesh_terms: D000328:Adult; D000818:Animals; D040501:Calgranulin A / Q000032:analysis / Q000378:metabolism*; D040502:Calgranulin B / Q000032:analysis / Q000378:metabolism*; D002457:Cell Extracts / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011499:Protein Processing, Post-Translational; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D002457:Cell Extracts; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C048496:N(6)-carboxymethyllysine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D008239:Lysine