Posttranslationally modified proteins as mediators of sustained intestinal inflammation

被引:76
作者
Andrassy, Martin
Igwe, John
Autschbach, Frank
Volz, Christian
Remppis, Andrew
Neurath, Markus F.
Schleicher, Erwin
Humpert, Per M.
Wendt, Thoralf
Liliensiek, Birgit
Morcos, Michael
Schiekofer, Stephan
Thiele, Kirsten
Chen, Jiang
Kientsch-Engel, Rose
Schmidt, Ann-Marie
Stremmel, Wolfgang
Stern, David M.
Katus, Hugo A.
Nawroth, Peter P.
Bierhaus, Angelika
机构
[1] Univ Heidelberg, Dept Med 1, D-69120 Heidelberg, Germany
[2] Univ Heidelberg, Dept Med 3, D-69120 Heidelberg, Germany
[3] Univ Heidelberg, Dept Med 4, D-69120 Heidelberg, Germany
[4] Univ Heidelberg, Inst Pathol, D-69120 Heidelberg, Germany
[5] Univ Mainz, Med Clin, Lab Immunol 1, D-6500 Mainz, Germany
[6] Univ Tubingen, Dept Med 4, D-72074 Tubingen, Germany
[7] Roche Diagnost GmbH, Penzberg, Germany
[8] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA
[9] Univ Cincinnati, Coll Med, Deans Off, Cincinnati, OH 45221 USA
关键词
D O I
10.2353/ajpath.2006.050713
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Oxidative and carbonyl stress leads to generation of NE-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-rcB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE(-/-) mice. A comparable upregulation 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.
引用
收藏
页码:1223 / 1237
页数:15
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