title: Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis.
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, 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.
authors.affiliation: Neuro-Gastroenterology & Nutrition Unit, Institut National de la Recherch Agronomique, Toulouse Cedex 9, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Dabek
authors.forename: Laurent
authors.initials: L
authors.lastname: Ferrier
authors.forename: Richard
authors.initials: R
authors.lastname: Roka
authors.forename: Krisztina
authors.initials: K
authors.lastname: Gecse
authors.forename: Anita
authors.initials: A
authors.lastname: Annahazi
authors.forename: Jacques
authors.initials: J
authors.lastname: Moreau
authors.forename: Jean
authors.initials: J
authors.lastname: Escourrou
authors.forename: Christel
authors.initials: C
authors.lastname: Cartier
authors.forename: Gilles
authors.initials: G
authors.lastname: Chaumaz
authors.forename: Mathilde
authors.initials: M
authors.lastname: Leveque
authors.forename: Afifa
authors.initials: A
authors.lastname: Ait-Belgnaoui
authors.forename: Tibor
authors.initials: T
authors.lastname: Wittmann
authors.forename: Vassilia
authors.initials: V
authors.lastname: Theodorou
authors.forename: Lionel
authors.initials: L
authors.lastname: Bueno
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000502:physiology; D003093:Colitis, Ulcerative / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018179:Receptors, Thrombin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D018179:Receptors, Thrombin; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534096:Ctsg protein, mouse; C112908:protease-activated receptor 4