Scientific Abstract
Proposal No. IBD-0076
Principal Investigator: Dirk Föll, M.D.
Applicant Organization: University Hospital of Münster (Germany)
Project Title: The role of the receptor for advanced glycation end products (RAGE) and its ligand S100A12 (EN-RAGE) in chronic inflammatory bowel disease
Period of Award: November 1, 2003 – June 30, 2006
The etiology and pathogenesis of chronic inflammatory bowel disease (IBD) is still poorly understood. An important mechanism in the initiation and perturbation of inflammation is the activation of endothelium, which is a crucial step for the recruitment of leukocytes into the inflamed tissue.
Binding of the neutrophilic calcium-binding protein S100A12 (calgranulin C; EN-RAGE) to the receptor for advanced glycation end products (RAGE) was demonstrated to induce upregulation of adhesion molecules on endothelium and production of cytokines by leukocytes. In mouse models, blocking the interaction of S100A12 with RAGE suppressed clinical and histological evidence of inflammation. Polymorphisms of the RAGE gene have been described as a factor amplifying inflammation in susceptible patients.
We have demonstrated that S100A12 is strongly expressed in inflamed tissue in IBD. S100A12 is secreted by neutrophils upon stimulation by TNF. On the other hand, S100A12 is able to induce the production of cytokines in inflammatory cells, thus establishing a positive feedback mechanism in orchestration with TNF. In IBD, an uncontrolled activity of this feedback loop might contribute to the perturbation of a systemic immune response. Serum concentrations of S100A12 are elevated in patients with these autoimmune diseases. We therefore hypothesize that S100A12 plays an important role during inflammation of chronic IBD.
Our aim is to evaluate S100A12 as a predictive serum marker for relapses or complications of IBD. Serum levels will be correlated with clinical and histological parameters to analyze if S100A12 correlates with disease course and outcome in different groups of patients. We will also elucidate the relevance of RAGE polymorphisms for the susceptibility to develop IBD or for the risk of complications during the course of the disease. Furthermore, we plan to investigate the exact RAGE-mediated proinflammatory effects of S100A12 on endothelium in IBD.
From our results, we hope to receive more insights into the pathophysiological basis of the leukocyte-endothelial interactions during inflammation in IBD. Furthermore, we will be able to improve the definition of S100A12 as a valuable serum marker for the disease activity of IBD. Finally, studies on the proinflammatory actions of S100A12 will give information on whether this protein may serve as an important cellular target for the development of new drugs that can be used to treat patients with chronic IBD.