Blockade of the Receptor for Advanced Glycation Endproducts Ameliorates Colitis
Abstracts
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INTRODUCTION: The Receptor for Advanced Glycation Endproducts (RAGE) has demonstrated increased expression in several inflammatory conditions. Blockade of RAGE in experimental inflammatory models has been shown to be beneficial. These studies were initiated to determine whether RAGE was involved in the generation of dextran sodium sulfate-induced colitis and the colitis initiated by the adminstration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). We tested the hypothesis that blockade of RAGE might ameliorate the proinflammatory effects of chemically-induced colitis. METHODS: C57BL/6 mice were given 1% DSS in their drinking water. Once colitis was induced, colonic tissue was retrieved and assayed for the presence of RAGE and its ligand, EN-RAGE, a prototypic S100/calgranulin. Subsequently, a soluble, truncated form of RAGE, comprising the extracellular domain, was adminstered to block access of ligands to RAGE. 2) C57BL/6 mice were given TNBS via enema. Mice were followed for survival, body weight, and histology. The soluble portion of RAGE was administered to determine whether RAGE blockade would abrogate the effects of TNBS. RESULTS: 1) In the DSS-induced colitis, both RAGE and EN-RAGE were present in the rectosigmoid tissue by immunoblotting. Adminstration of soluble RAGE was effective in prolonging survival, diminishing the severity of inflammation and weight loss, suppressing plasma levels of TNF-alpha, and preserving colonic expression of IL-10. 2) In TNBS-induced colitis, adminstration of soluble RAGE produced a trend towards prolonged survival, while diminishing histopathology. CONCLUSION: Blockade of RAGE may be beneficial in suppression of inflammation and tissue damage due to colitis. |
