Luminal Cathepsin G and Protease-Activated Receptor 4
Open accessAbstract
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.
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In Crohn's disease and ulcerative colitis patients, increased host serine protease production from colonic tissue has been reported.
“In both CD and UC patients, increased host serine protease production from colonic tissue have been reported.27,28”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [28]
PAR-4 activation by cathepsin G, a protease elevated in fecal samples from UC patients, led to increased mucosal permeability and inflammation in vivo in mice.
“PAR-4 activation by cathepsin G, a protease that is elevated in fecal samples from UC patients, led to increased mucosal permeability and inflammation in vivo in mice.28”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [28]
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Cites
Measurement of Cutaneous Inflammation: Estimation of Neutrophil Content with an Enzyme Marker
Bradley, P. P., Priebat, D. A., Christensen, R. D., & Rothstein, G. (1982) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12506462 · Cited by 3,628 · see citing works
Podolsky, D. K. (2002) · New England Journal of Medicine · doi:10.1056/nejmra020831 · Cited by 3,183 · see citing works
The fundamental basis of inflammatory bowel disease
Strober, W., Fuss, I. J., & Mannon, P. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30587 · Cited by 1,310 · see citing works
Zeißig, S., Bürgel, N., Günzel, D., Richter, J. F., Mankertz, J., Wahnschaffe, U., Kroesen, A. J., Zeitz, M., Fromm, M., & Schulzke, J. (2006) · Gut · doi:10.1136/gut.2006.094375 · Cited by 1,218 · see citing works
Cloning and characterization of human protease-activated receptor 4
Xu, W., Andersen, H., Whitmore, T. E., Presnell, S., Yee, D. P., Ching, A. F. T., Gilbert, T., Davie, E. W., & Foster, D. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.12.6642 · Cited by 815 · see citing works
Inflammatory Bowel Disease and Adenomas in Mice Expressing a Dominant Negative N-Cadherin
Hermiston, M. L., & Gordon, J. I. (1995) · Science · doi:10.1126/science.270.5239.1203 · Cited by 669 · see citing works
International Union of Pharmacology. XXVIII. Proteinase-Activated Receptors
Hollenberg, M. D., & Compton, S. J. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.2.203 · Cited by 441 · see citing works
Lampe, B., Barthel, B., Coupland, S. E., Riecken, E.-O., & Rosewicz, S. (2000) · Gut · doi:10.1136/gut.47.1.63 · Cited by 386 · see citing works
Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2.
Cénac, N., Coelho, A., Nguyen, C., Compton, S., Andrade-Gordon, P., MacNaughton, W., Wallace, J., Hollenberg, M., Bunnett, N., Garcia-Villar, R., et al. (2002) · American Journal of Pathology · doi:10.1016/s0002-9440(10)64466-5 · Cited by 386 · see citing works
Self-citationCathepsin G Activates Protease-activated Receptor-4 in Human Platelets
Sambrano, G. R., Huang, W., Faruqi, T. R., Mahrus, S., Craik, C. S., & Coughlin, S. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.10.6819 · Cited by 341 · see citing works
Gecse, K., Róka, R., Ferrier, L., Leveque, M., Eutamene, H., Cartier, C., Ait-Belgnaoui, A., Rosztóczy, A., Izbéki, F., Fioramonti, J., et al. (2008) · Gut · doi:10.1136/gut.2007.140210 · Cited by 314 · see citing works
Self-citationRole of the intestinal barrier in inflammatory bowel disease
Laukoetter, M. G., Nava, P., & Nusrat, A. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.401 · Cited by 301 · see citing works
Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation
Covic, L., Misra, M. V., Badar, J., Singh, C., & Kuliopulos, A. (2002) · Nature Medicine · doi:10.1038/nm760 · Cited by 273 · see citing works
Blocking the Protease-Activated Receptor 1-4 Heterodimer in Platelet-Mediated Thrombosis
Leger, A. J., Jacques, S. L., Badar, J., et al. (2006) · Circulation · doi:10.1161/circulationaha.105.587758 · Cited by 218 · see citing works
Vergnolle, N., Derian, C. K., D’Andrea, M. R., Steinhoff, M. S., & Andrade‐Gordon, P. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.3.1467 · Cited by 155 · see citing works
Chin, A. C., Vergnolle, N., MacNaughton, W. K., Wallace, J. L., Hollenberg, M. D., & Buret, A. G. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1831452100 · Cited by 149 · see citing works
Róka, R., Rosztoczy, A. I., Leveque, M., Izbéki, F., Nagy, F. T., Molnár, T., Lonovics, J., Villar, R. G., Fioramonti, J., Wittmann, T., et al. (2007) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2006.12.004 · Cited by 132 · see citing works
Self-citationInflammatory bowel disease: is it really just another break in the wall?: Figure 1
Weber, C. R., & Turner, J. R. (2006) · Gut · doi:10.1136/gut.2006.104182 · Cited by 132 · see citing works
Benefits of Zataria multiflora Boiss in Experimental Model of Mouse Inflammatory Bowel Disease
Nakhai, L. A., Mohammadirad, A., Yasa, N., et al. (2006) · Evidence-based Complementary and Alternative Medicine · doi:10.1093/ecam/nel051 · Cited by 132 · see citing works
Menzel, K., Hausmann, M., Obermeier, F., Schreiter, K., Dunger, N., Bataille, F., Falk, W., Schölmerich, J., Herfarth, H. H., & Rogler, G. (2006) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2006.03188.x · Cited by 130 · see citing works
Carlson, M., Raab, Y., Sevéus, L., Xu, S., Hällgren, R., & Venge, P. (2002) · Gut · doi:10.1136/gut.50.4.501 · Cited by 129 · see citing works
Normal Neutrophil Function in Cathepsin G-Deficient Mice
MacIvor, D. M., Shapiro, S. D., Pham, C. T. N., Belaaouaj, A., Abraham, S. N., & Ley, T. J. (1999) · Blood · doi:10.1182/blood.v94.12.4282 · Cited by 120 · see citing works
The antithrombotic effect of aprotinin: actions mediated via the protease-activated receptor 1
Poullis, M. P., Manning, R. A., Laffan, M., et al. (2000) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1067/mtc.2000.108531 · Cited by 118 · see citing works
Neutrophil Transepithelial Migration and Epithelial Barrier Function in IBD
Chin, A. C., & Parkos, C. A. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1326.018 · Cited by 114 · see citing works
Hanai, H., Takeuchi, K., Iida, T., et al. (2004) · Digestive Diseases and Sciences · doi:10.1023/b:ddas.0000042243.47279.87 · Cited by 111 · see citing works
Tarlton, J. F., Whiting, C. V., Tunmore, D., Bregenholt, S., Reimann, J., Claësson, M. H., & Bland, P. W. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64831-6 · Cited by 103 · see citing works
Houle, S., Papez, M. D., Ferazzini, M., Hollenberg, M. D., & Vergnolle, N. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706371 · Cited by 97 · see citing works
de Leeuw, E. D., Li, X., & Lu, W.-Y. (2006) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2006.00313.x · Cited by 73 · see citing works
Slofstra, S. H., Bijlsma, M. F., Groot, A. P., Reitsma, P. H., Lindhout, T., ten Cate, H., & Spek, C. A. (2007) · Blood · doi:10.1182/blood-2007-02-075440 · Cited by 66 · see citing works
Sabri, A., Alcott, S., Elouardighi, H., Pak, E. S., Derian, C. K., Andrade‐Gordon, P., Kinnally, K. W., & Steinberg, S. F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302718200 · Cited by 64 · see citing works
Shimoda, N., Fukazawa, N., Nonomura, K., & Fairchild, R. L. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.060486 · Cited by 60 · see citing works
Protease-activated receptors: protease signaling in the gastrointestinal tract
Amadesi, S., & Bunnett, N. W. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.08.004 · Cited by 49 · see citing works
Le-Barillec, K., Pidard, D., Balloy, V., & Chignard, M. (2000) · Journal of Leukocyte Biology · doi:10.1189/jlb.68.2.209 · Cited by 37 · see citing works
Robinson, C. E., Kottapalli, V., D'astice, M., et al. (1997) · Journal of Laboratory and Clinical Medicine · doi:10.1016/s0022-2143(97)90109-8 · Cited by 24 · see citing works
Molecular cloning of the rat proteinase-activated receptor 4 (PAR4)
Hoogerwerf, W. A., Hellmich, H. L., Micci, M. A., Winston, J. H., Zou, L., & Pasricha, P. J. (2002) · BMC Molecular Biology · doi:10.1186/1471-2199-3-2 · Cited by 23 · see citing works
Effect of Aprotinin and Recombinant Variants on Platelet Protease-Activated Receptor 1 Activation
Day, J. R., Haskard, D. O., Taylor, K. M., et al. (2006) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2005.07.056 · Cited by 21 · see citing works
SETHI, A. S., Lees, D. M., Douthwaite, J. A., et al. (2005) · Clinical Science · doi:10.1042/cs20040237 · Cited by 17 · see citing works
Anti-cathepsin G antibodies in the sera of patients with ulcerative colitis
Kuwana, T., Sato, Y., Saka, M., et al. (2000) · Journal of Gastroenterology · doi:10.1007/s005350070047 · Cited by 17 · see citing works
Abnormalities in the upper gastrointestinal tract in inflammatory bowel disease
Ando, T., Nobata, K., Watanabe, O., et al. (2007) · Inflammopharmacology · doi:10.1007/s10787-006-0735-1 · Cited by 14 · see citing works
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Cattaruzza, F., Lyo, V., Jones, E., Pham, D., Hawkins, J., Kirkwood, K., Valdez–Morales, E., Ibeakanma, C., Vanner, S. J., Bogyo, M., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.035 · Cited by 103 · see citing works
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Jablaoui, A., Kriaa, A., Mkaouar, H., Akermi, N., Soussou, S., Wysocka, M., Wołoszyn, D., Amouri, A., Gargouri, A., Maguin, E., et al. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00021 · Cited by 101 · see citing works
Annaházi, A., Ferrier, L., Bézirard, V., Lévêque, M., Eutamène, H., Ait-Belgnaoui, A., Coëffier, M., Ducrotté, P., Róka, R., Inczefi, O., et al. (2013) · American Journal of Gastroenterology · doi:10.1038/ajg.2013.152 · Cited by 96 · see citing works
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Denadai-Souza, A., Bonnart, C., Tapias, N. S., Marcellin, M., Gilmore, B., Alric, L., Bonnet, D., Burlet-Schiltz, O., Hollenberg, M. D., Vergnolle, N., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-26282-y · Cited by 91 · see citing works
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- Authors
- Dabek, M., Ferrier, L., Roka, R., Gecse, K., Annahazi, A., Moreau, J., Escourrou, J., Cartier, C., Chaumaz, G., Leveque, M., Ait-Belgnaoui, A., Wittmann, T., Theodorou, V., & Bueno, L.
- Affiliations
- Institut National de la Recherche Agronomique (FR)
- University of Szeged (HU)
- Hôpital Rangueil (FR)
- Corresponding author
- Bueno, Lionel
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 175
- Issue
- 1
- Pages
- 207-214
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2708807
- OpenAlex
- W1562821701
- Cited by
- 73
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 8 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 2
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Institut National de la Recherche Agronomique
- Agence Nationale pour la Gestion des Déchets Radioactifs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- cathepsin G, PAR4, ulcerative colitis, colonic epithelial barrier, neutrophil serine proteases, fecal supernatants, myeloperoxidase, neutrophil infiltration
- MeSH terms
- Adult, Aged, Animals, Cathepsins, Cell Membrane Permeability, Colitis, Ulcerative, Feces, Humans, Immunohistochemistry, Intestinal Mucosa, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Middle Aged, Serine Endopeptidases, Blotting, Western, Receptors, Thrombin, Reverse Transcriptase Polymerase Chain Reaction, Mice, Cathepsin G
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