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.

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

“…These include activation of TAFI, that plays important roles in coagulation, inflammation, and extracellular matrix remodeling (47,48), and binding of the highly pro-inflammatory HMGB1 DNA binding protein (sometimes referred to as the "nuclear weapon in the immune system's arsenal"). HMGB1 binds to the cell surface receptor for advanced glycation endproducts (RAGE), which is involved in induction of fibrosis and intestinal inflammation and mucosal barrier loss (49)(50)(51). It is interesting to speculate that HMGB1 may be a particularly important aspect of TM in regulating the transition from acute inflammation to chronic inflammation and intestinal fibrosis.…”

Critical role of RAGE and HMGB1 in inflammatory heart disease

“…The binding activity of p65-NF-κB in nuclear protein extracts (70 μg) of heart tissue was assayed with 32 P radioactively labeled oligonucleotide sequences (5′-AGT TGA GGG GAC TTT CCC AGG C-3′) at 50,000 cpm by autoradiography. The experiment is based on electrophoretic mobility of a protein-nucleic acid complex, which migrates more slowly than the corresponding free nucleic acid, and was performed as previously described (57).…”

Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes

“…RAGE is pattern recognition receptor (1) that is able to bind a chemically diverse range of AGEs and other non-AGE ligands, including s100/calgranulins, HMGB1, and ␤-sheet fibrils. In atherosclerotic vascular disease, the expression of RAGE is focally increased (14,15,21), paralleling an accumulation in RAGE ligands. The major RAGE ligand in the context of diabetes remains to be established.…”