Proteolytic Regulation of the Intestinal Epithelial Barrier: Mechanisms and Interventions

Abstract : Inflammatory bowel diseases are characterized by chronic, progressive and destructive inflammation of the gastrointestinal tract. The two main forms of inflammatory bowel diseases (IBD), Crohn s disease and Ulcerative Colitis, currently affect over 1 million Americans including military personnel, and the incidence among aging veterans is rising. Compromised intestinal barrier function underlies much of the pathology associated with many inflammatory bowel diseases. Matriptase is a membrane-anchored serine protease encoded by the Suppression of Tumorigenicity-14 (ST14) gene that is required for epithelial barrier homeostasis. The project uses the St14 hypomorphic mouse model of matriptase deficiency to 1) determine molecular mechanisms that mediate matriptase protection during DSS-induced experimental inflammatory colitis, 2) define molecular mechanisms by which matriptase becomes decreased during inflammatory colitis, and 3) investigate the importance of matriptase to cytokine induced barrier loss using an in vitro model of intestinal barrier repair. Our data demonstrate that the matriptase barrier forming pathway is down-regulated at the transcriptional and protein levels by cytokines produced during inflammatory colitis. Further, matriptase acts downstream of prostasin to mediate barrier formation and both of these proteases are coordinately regulated. The loss of this pathway is likely to facilitate intestinal barrier disruption in human IBD.