Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis.

Abstract

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.

• Authors: Jean-Paul Motta, Laurent Magne, Delphyne Descamps, Corinne Rolland, Camila Squarzoni-Dale, Perrine Rousset, Laurence Martin, Nicolas Cenac, Viviane Balloy, Michel Huerre, Leopold F Fröhlich, Dieter Jenne, Julien Wartelle, Azzaq Belaaouaj, Emmanuel Mas, Jean-Pierre Vinel, Laurent Alric, Michel Chignard, Nathalie Vergnolle, Jean-Michel Sallenave
• Journal: Gastroenterology (Gastroenterology) Vol. 140 Issue 4 Pg. 1272-82 (Apr 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21199654 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chemokines
• Cytokines
• Elafin
• NF-kappa B
• Protease Inhibitors
• Serine Proteinase Inhibitors
• Leukocyte Elastase
• Myeloblastin

Topics

• Adenoviridae (genetics)
• Animals
• Caco-2 Cells
• Chemokines (metabolism)
• Colitis (genetics, metabolism, therapy)
• Cytokines (metabolism)
• Elafin (genetics, metabolism)
• Gene Expression (physiology)
• Genetic Therapy (methods)
• HT29 Cells
• Humans
• Leukocyte Elastase (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• Myeloblastin (metabolism)
• NF-kappa B (metabolism)
• Neutrophils (enzymology, immunology)
• Protease Inhibitors (metabolism)
• Serine Proteinase Inhibitors (metabolism)