Published online before print June 15, 2009

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(American Journal of Pathology. 2009;175:207-214.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080986

Luminal Cathepsin G and Protease-Activated Receptor 4

A Duet Involved in Alterations of the Colonic Epithelial Barrier in Ulcerative Colitis

Marta Dabek^*, Laurent Ferrier^*, Richard Roka, Krisztina Gecse, Anita Annahazi^*, Jacques Moreau, Jean Escourrou, Christel Cartier^*, Gilles Chaumaz^*, Mathilde Leveque^*, Afifa Ait-Belgnaoui^*, Tibor Wittmann, Vassilia Theodorou and Lionel Bueno^*

From the Neuro-Gastroenterology & Nutrition Unit,^* UMR 1054, l’Institut National de la Reserche Agronomique (INRA), Toulouse, France; the First Department of Internal Medicine, University of Szeged, Szeged, Hungary; the Department of Hepato-Gastroenterology, Centre Hospitalier Universitaire Rangueil (CHU), Toulouse, France; and the Neuro-Gastroenterology & Nutrition Unit, UMR 1054, University of Toulouse, El-Purpan, Toulouse, France

Impairment of the colonic epithelial barrier and neutrophil infiltration are common features of inflammatory bowel disease. Luminal proteases affect colonic permeability through protease-activated receptors (PARs). We evaluated: (i) whether fecal supernatants from patients with ulcerative colitis (UC) trigger alterations of colonic paracellular permeability and inflammation, and (ii) the roles of cathepsin G (Cat-G), a neutrophil serine protease, and its selective receptor, PAR₄, in these processes. Expression levels of both PAR₄ and Cat-G were determined in colonic biopsies from UC and healthy subjects. The effects of UC fecal supernatants on colonic paracellular permeability were measured in murine colonic strips. Involvement of Cat-G and PAR₄ was evaluated using pepducin P4pal-10 and specific Cat-G inhibitor (SCGI), respectively. In addition, the effect of PAR₄-activating peptide was assessed. UC fecal supernatants, either untreated or pretreated with SCGI, were infused into mice, and myeloperoxidase activity was determined. PAR₄ was found to be overexpressed in UC colonic biopsies. Increased colonic paracellular permeability that was triggered by UC fecal supernatants was blocked by both SCGI (77%) and P4pal-10 (85%). Intracolonic infusion of UC fecal supernatants into mice increased myeloperoxidase activity. This effect was abolished by SCGI. These observations support that both Cat-G and PAR₄ play key roles in generating and/or amplifying relapses in UC and provide a rationale for the development of new therapeutic agents in the treatment of this disease.