Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis
| Autor: | Perrine Rousset, Michel Huerre, Leopold F. Fröhlich, Camila Squarzoni Dale, Jean-Michel Sallenave, Laurence Martin, Corinne Rolland, Julien Wartelle, Delphyne Descamps, Laurent Alric, Jean-Paul Motta, Dieter E. Jenne, Laurent Magne, Jean-Pierre Vinel, Emmanuel Mas, Michel Chignard, Viviane Balloy, Nicolas Cenac, Nathalie Vergnolle, Azzaq Belaaouaj |
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| Přispěvatelé: | Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Défense innée et inflammation, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Histotechnologie et Pathologie, Institut Pasteur [Paris], Department of Neuroimmunology, Max-Planck-Institut, Inflammation et immunité de l'épithélium respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53, Division of Gastroenterology, Hepatology and Nutrition, Hôpital pour enfants de Toulouse, Service de Gastro-entérologie - Hépatologie [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Research was supported by grants from the Bettencourt-Schueller Foundation and the INSERM-Avenir (to N.V.), the Schlumberger Foundation (to N.V.), the Agence Nationale pour la Recherche (to N.V.), the Fondation pour la Recherche Medicale (to N.V.), the region Midi-Pyrenées (to J.-P.M.), and the Canadian Association of Gastroenterology (to C.S.-D.). Laurent Magne holds an ATER (temporary teaching fellow) position from the Université Paris 7-Diderot., The authors are indebted to Ms B. Solhonne (Institut Pasteur/INSERM U874, Paris, France), Ms M.-A. Nicola (Institut Pasteur, Paris), and to Professor Z. Xing (McMaster University, Hamilton, Canada) for stimulating discussions and help during the study., Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150) (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), UFR Sciences du Vivant [Paris] (SDV), Université Paris Diderot - Paris 7 (UPD7), Institute of Pathology [Graz, Austria], University of Graz, Department of Neuroimmunology [Munich, Germany], Max Planck Institute of Neurobiology, Pôle Digestif [purpan], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Research was supported by grants from the Bettencourt-Schueller Foundation and the INSERM-Avenir (to N.V.), the Schlumberger Foundation (to N.V.), the Agence Nationale pour la Recherche (to N.V.), the Fondation pour la Recherche Medicale (to N.V.), the region Midi-Pyrenées (to J.-P.M.) ,and the Canadian Association of Gastroenterology (to C.S.-D.). Laurent Magne holds an ATER (temporary teaching fellow) position from the Université Paris7-Diderot., Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Service Gastroentérologie, hépatologie nutrition, diabétologie et maladies héréditaires du métabolisme pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Pôle Maladies de l'appareil digestif [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Sallenave, Jean-Michel |
| Rok vydání: | 2010 |
| Předmět: |
MESH: Protease Inhibitors/metabolism
Male Neutrophils medicine.medical_treatment [SDV]Life Sciences [q-bio] MESH: HT29 Cells Gene Expression MESH: Adenoviridae/genetics Inflammatory bowel disease MESH: Colitis*/genetics Mice 0302 clinical medicine MESH: Genetic Therapy/methods MESH: Leukocyte Elastase/metabolism MESH: Colitis*/metabolism MESH: Animals MESH: Chemokines/metabolism 0303 health sciences MESH: Mice Inbred CBA biology MESH: Elafin/genetics Chemistry Elastase Gastroenterology NF-kappa B Proteases Colitis 3. Good health Elafin Neutrophil elastase MESH: Neutrophils/enzymology [SDV.IMM]Life Sciences [q-bio]/Immunology Cytokines 030211 gastroenterology & hepatology MESH: Caco-2 Cells MESH: NF-kappa B/metabolism Chemokines HT29 Cells Serine Proteinase Inhibitors [SDV.IMM] Life Sciences [q-bio]/Immunology MESH: Mice Transgenic Myeloblastin Mice Transgenic Protein degradation MESH: Elafin/metabolism Adenoviridae 03 medical and health sciences MESH: Serine Proteinase Inhibitors/metabolism MESH: Mice Inbred C57BL medicine Animals Humans Protease Inhibitors MESH: Gene Expression/physiology MESH: Mice 030304 developmental biology Inflammation Protease MESH: Humans Hepatology Inflammatory Bowel Disease [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Genetic Therapy medicine.disease digestive system diseases MESH: Male Mice Inbred C57BL MESH: Myeloblastin/metabolism MESH: Colitis*/therapy Immunology MESH: Neutrophils/immunology biology.protein Cancer research Mice Inbred CBA MESH: Cytokines/metabolism Caco-2 Cells Leukocyte Elastase |
| Zdroj: | Gastroenterology Gastroenterology, WB Saunders, 2010, 140 (4), pp.1272-82. ⟨10.1053/j.gastro.2010.12.050⟩ Gastroenterology, WB Saunders, 2011, 140 (4), pp.1272-1282. ⟨10.1053/j.gastro.2010.12.050⟩ Gastroenterology, 2010, 140 (4), pp.1272-82. ⟨10.1053/j.gastro.2010.12.050⟩ |
| ISSN: | 1528-0012 0016-5085 |
| Popis: | International audience; BACKGROUND & AIMS:Colonic tissues of patients with inflammatory bowel disease have been reported to have increased proteolytic activity, but no studies have clearly addressed the role of the balance between proteases and antiproteases in the pathogenesis of colitis. We investigated the role of Elafin, a serine protease inhibitor expressed by skin and mucosal surfaces in human inflammatory conditions, and the proteases neutrophil elastase (NE) and proteinase-3 (PR-3) in mice with colitis.METHODS:We studied mice with heterozygous disruptions in NE and PR-3, mice that express human elafin (an inhibitor of NE and PR-3), and naïve mice that received intracolonic adenoviral vectors that express elafin. Trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulphate (DSS) was used to induce colitis. Protease, cytokine levels, and NF-κB activity were measured in colons of mice. Caco-2 and HT29 cells were studied in assays for cytokine expression, permeability, and NF-κB activity.RESULTS:Elafin expression or delivery re-equilibrated the proteolytic balance in inflamed colons of mice. In mice given TNBS or DSS, transgenic expression of elafin or disruption of NE and PR-3 protected against the development of colitis. Similarly, adenoviral delivery of Elafin significantly inhibited inflammatory parameters. Elafin modulated a variety of inflammatory mediators in vitro and in vivo and strengthened intestinal epithelial barrier functions.CONCLUSIONS:The protease inhibitor Elafin prevents intestinal inflammation in mouse models of colitis and might be developed as a therapeutic agent for inflammatory bowel disease. |
| Databáze: | OpenAIRE |
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