Luminal Cathepsin G and Protease-Activated Receptor 4

• Published in: The American journal of pathology Vol. 175; no. 1; pp. 207 - 214
• Main Authors: Dabek, Marta, Ferrier, Laurent, Roka, Richard, Gecse, Krisztina, Annahazi, Anita, Moreau, Jacques, Escourrou, Jean, Cartier, Christel, Chaumaz, Gilles, Leveque, Mathilde, Ait-Belgnaoui, Afifa, Wittmann, Tibor, Theodorou, Vassilia, Bueno, Lionel
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 2009
• Subjects: Pathology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080986

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, PAR 4, in these processes. Expression levels of both PAR 4 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 PAR 4 was evaluated using pepducin P4pal-10 and specific Cat-G inhibitor (SCGI), respectively. In addition, the effect of PAR 4-activating peptide was assessed. UC fecal supernatants, either untreated or pretreated with SCGI, were infused into mice, and myeloperoxidase activity was determined. PAR 4 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 PAR 4 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.