Posttranslationally modified proteins as mediators of sustained intestinal inflammation.
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.
Andrassy
Martin
M
Department of Medicine I, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Igwe
John
J
Autschbach
Frank
F
Volz
Christian
C
Remppis
Andrew
A
Neurath
Markus F
MF
Schleicher
Erwin
E
Humpert
Per M
PM
Wendt
Thoralf
T
Liliensiek
Birgit
B
Morcos
Michael
M
Schiekofer
Stephan
S
Thiele
Kirsten
K
Chen
Jiang
J
Kientsch-Engel
Rose
R
Schmidt
Ann-Marie
AM
Stremmel
Wolfgang
W
Stern
David M
DM
Katus
Hugo A
HA
Nawroth
Peter P
PP
Bierhaus
Angelika
A
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
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