3rd Annual BMRP Investigator Meeting - Abstract
The Role of the Pro-inflammatory Mediator S100A12 in Inflammatory Bowel Disease
Dirk Foell1,a, Dorothee Viemann1, Jan Ehrchen2, Jan Heidemann3, Pia Lebietz3, Torsten Kucharzik3 and Johannes Roth1
1Department of Pediatrics, 2Institute of Experimental Dermatology and 3Department of Medicine B, University of Muenster (Muenster, Germany)
Objectives: S100A12 is a pro-inflammatory protein expressed and secreted by neutrophils. Binding of released S100A12 to the receptor for advanced glycosylation end products (RAGE) activates endothelium and leukocytes. Blocking S100A12 activity revealed promising therapeutic effects in various murine models of colitis. In previous studies, we found that inflammatory bowel disease (IBD) patients in remission who have residual inflammation not leading to clinically apparent signs of disease activity nevertheless had elevated S100A12 serum levels.
Methods: S100A12-induced effects on human microvascular endothelial cells (HMECs) and human intestinal microvascular endothelial cells (HIMECs) were analyzed. The association of the G82S polymorphism of the RAGE gene with IBD has been studied in a total of 635 DNA samples from patients with IBD and 538 controls. Sensitivity of S100A12 serum measurements for the detection of relapsing disease activity was analyzed by ELISA in a total of 433 serum samples from 121 IBD patients who were followed up prospectively.
Results: Stimulation of HMECs and HIMECs with S100A12 increased surface expression of VCAM-1 and ICAM-1, decreased endothelial resistance and promoted transendothelial migration of phagocytes. After S100A12-stimulation, pro-inflammatory genes were upregulated in endothelial cells. Effects of blocking antibodies and soluble receptor constructs are currently being investigated. The G82S RAGE polymporphism was more frequent in patients with Crohn’s disease. S100A12 serum levels were significantly elevated in patients with inactive IBD prior relapses (290 ng/ml versus 145 ng/ml in patients in stable remission).
Conclusions: Released S100A12 is a mediator that activates immune cells critical to pathogenesis of colitis. The pro-inflammatory properties of S100A12 make this neutrophilic protein an attractive target for anti-inflammatory therapies. Moreover, the G82S RAGE polymporphism may be associated with Crohn’s disease. S100A12 may provide an excellent serum marker for the early detection of relapsing colitis.
aPrincipal Investigator