title: Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis.
abstract: OBJECTIVE
  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.affiliation: Inserm, U1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Motta
authors.forename: Laurent
authors.initials: L
authors.lastname: Magne
authors.forename: Delphyne
authors.initials: D
authors.lastname: Descamps
authors.forename: Corinne
authors.initials: C
authors.lastname: Rolland
authors.forename: Camila
authors.initials: C
authors.lastname: Squarzoni-Dale
authors.forename: Perrine
authors.initials: P
authors.lastname: Rousset
authors.forename: Laurence
authors.initials: L
authors.lastname: Martin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.forename: Viviane
authors.initials: V
authors.lastname: Balloy
authors.forename: Michel
authors.initials: M
authors.lastname: Huerre
authors.forename: Leopold F
authors.initials: LF
authors.lastname: Fröhlich
authors.forename: Dieter
authors.initials: D
authors.lastname: Jenne
authors.forename: Julien
authors.initials: J
authors.lastname: Wartelle
authors.forename: Azzaq
authors.initials: A
authors.lastname: Belaaouaj
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mas
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vinel
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018938:Caco-2 Cells; D018925:Chemokines / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D016207:Cytokines / Q000378:metabolism; D053492:Elafin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D019073:HT29 Cells; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D053146:Myeloblastin / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D011480:Protease Inhibitors / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D053492:Elafin; D016328:NF-kappa B; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase; D053146:Myeloblastin