4th Annual BMRP Investigator Meeting - Abstract

Neutrophil-Derived S100A12 (EN-RAGE):  Molecular Basis of its Expression, Secretion, Receptor-Binding, and its Role in Inflammatory Bowel Disease

Dirk Foell^1,a, Helmut Wittkowski¹, Frauke Friedrichs², Jochen Hampe³, Jost Langhorst⁴, Bernd Weigle⁵, Geetha Srikrishna⁶, Hudson Freeze⁶, Monika Stoll², Torsten Kucharzik⁷, Stefan Schreiber³, Johannes Roth<sup>1

1</sup>Department of Pediatrics and ⁷Department of Internal Medicine B, University of Muenster (Muenster, Germany); ²Leibniz-Institute for Arteriosclerosis Research (Muenster, Germany); ³Institute for Clinical Molecular Biology and Department of General Internal Medicine, Christian-Albrecht-University (Kiel, Germany); ⁴Department of Internal Medicine, University of Essen (Essen, Germany); ⁵EUCODIS GmbH (Vienna, Austria); ⁶Burnham Institute (La Jolla, California, U.S.A.)

 Neutrophil-derived S100A12 is a mediator that activates immune cells critical to the pathogenesis of colitis.  S100A12 expression and secretion are actively regulated processes.  Like IL-1, S100A12 is secreted via an alternative pathway.  Released S100A12 forms hexamers with high affinity to the Receptor for Advanced Glycation End products (RAGE).  Binding of S100A12 to RAGE leads to activation of intestinal endothelium and monocytes.  S100A12 constitutes a positive feedback loop with IL-1 and TNF.  Moreover, RAGE polymorphism may be associated with Crohn’s disease (CD).  The A allele of the RAGE promotor polymorphism at position -374 is negatively associated with CD.  We conclude that the 374T/A variant leading to facilitated RAGE gene transcription may protect from developing CD by augmenting innate immune mechanisms and increasing levels of soluble RAGE, which neutralizes pro-inflammatory mediators.  Serum and fecal S100A12 levels correlate strongly to local S100A12 expression and disease activity.  S100A12 is an excellent serum and fecal marker for disease monitoring in inflammatory bowel disease.

 ^aPrincipal Investigator