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, R. Róka, Krisztina Gecse, Anita Annahazi, Jacques Moreau, Jean Escourrou, Christel Cartier, Gilles Chaumaz, Mathilde Leveque, Afifa Ait-Belgnaoui, T. Wittmann, Vassilia Theodorou, Lionel Bueno

Research output: Contribution to journalArticle

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Abstract

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 PAR 4-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.

Original languageEnglish
Pages (from-to)207-214
Number of pages8
JournalAmerican Journal of Pathology
Volume175
Issue number1
DOIs
Publication statusPublished - Jul 2009

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Cathepsin G
Ulcerative Colitis
Permeability
Cats
Peroxidase
Proteinase-Activated Receptors
Biopsy
Neutrophil Infiltration
protease-activated receptor 4
Serine Proteases
Inflammatory Bowel Diseases
Healthy Volunteers
Neutrophils
Peptide Hydrolases
Inflammation
Recurrence
Peptides

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Luminal cathepsin G and protease-activated§ receptor 4 : A duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. / Dabek, Marta; Ferrier, Laurent; Róka, R.; Gecse, Krisztina; Annahazi, Anita; Moreau, Jacques; Escourrou, Jean; Cartier, Christel; Chaumaz, Gilles; Leveque, Mathilde; Ait-Belgnaoui, Afifa; Wittmann, T.; Theodorou, Vassilia; Bueno, Lionel.

In: American Journal of Pathology, Vol. 175, No. 1, 07.2009, p. 207-214.

Research output: Contribution to journalArticle

Dabek, M, Ferrier, L, Róka, R, Gecse, K, Annahazi, A, Moreau, J, Escourrou, J, Cartier, C, Chaumaz, G, Leveque, M, Ait-Belgnaoui, A, Wittmann, T, Theodorou, V & Bueno, L 2009, 'Luminal cathepsin G and protease-activated§ receptor 4: A duet involved in alterations of the colonic epithelial barrier in ulcerative colitis', American Journal of Pathology, vol. 175, no. 1, pp. 207-214. https://doi.org/10.2353/ajpath.2009.080986
Dabek, Marta ; Ferrier, Laurent ; Róka, R. ; Gecse, Krisztina ; Annahazi, Anita ; Moreau, Jacques ; Escourrou, Jean ; Cartier, Christel ; Chaumaz, Gilles ; Leveque, Mathilde ; Ait-Belgnaoui, Afifa ; Wittmann, T. ; Theodorou, Vassilia ; Bueno, Lionel. / Luminal cathepsin G and protease-activated§ receptor 4 : A duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. In: American Journal of Pathology. 2009 ; Vol. 175, No. 1. pp. 207-214.
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