TY - JOUR
T1 - Luminal cathepsin G and protease-activated§ receptor 4
T2 - A duet involved in alterations of the colonic epithelial barrier in ulcerative colitis
AU - Dabek, Marta
AU - Ferrier, Laurent
AU - Roka, Richard
AU - Gecse, Krisztina
AU - Annahazi, Anita
AU - Moreau, Jacques
AU - Escourrou, Jean
AU - Cartier, Christel
AU - Chaumaz, Gilles
AU - Leveque, Mathilde
AU - Ait-Belgnaoui, Afifa
AU - Wittmann, Tibor
AU - Theodorou, Vassilia
AU - Bueno, Lionel
N1 - Funding Information: Supported by grants from INRA, BREMICI, and Association François Aupetit. M.D. was supported by a post-doc fellowship grant from INRA. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2009/7
Y1 - 2009/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=67649990850&partnerID=8YFLogxK
U2 - https://doi.org/10.2353/ajpath.2009.080986
DO - https://doi.org/10.2353/ajpath.2009.080986
M3 - Article
C2 - 19528350
SN - 0002-9440
VL - 175
SP - 207
EP - 214
JO - American journal of pathology
JF - American journal of pathology
IS - 1
ER -