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Novel Role of the Serine Protease Inhibitor Elafin in Gluten-Related Disorders

Galipeau, Heather J BHSc1; Wiepjes, Michelle MSc1; Motta, Jean-Paul PhD2, 3, 4; Schulz, Jessica D MSc5; Jury, Jennifer MSc1; Natividad, Jane M PhD1; Pinto-Sanchez, Ines MD1; Sinclair, Daniel BSc1; Rousset, Perrine MSc2, 3, 4; Martin-Rosique, Rebeca PhD6; Bermudez-Humaran, Luis PhD6; Leroux, Jean Christophe PhD5; Murray, Joseph A MD7; Smecuol, Edgardo MD8; Bai, Julio C MD8; Vergnolle, Nathalie PhD2, 3, 4; Langella, Philippe PhD6; Verdu, Elena F MD, PhD1

American Journal of Gastroenterology: May 2014 - Volume 109 - Issue 5 - p 748–756
doi: 10.1038/ajg.2014.48
Colon/Small Bowel
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OBJECTIVES: Elafin, an endogenous serine protease inhibitor, modulates colonic inflammation. We investigated the role of elafin in celiac disease (CD) using human small intestinal tissues andin vitroassays of gliadin deamidation. We also investigated the potential beneficial effects of elafin in a mouse model of gluten sensitivity.

METHODS: Epithelial elafin expression in the small intestine of patients with active CD, treated CD, and controls without CD was determined by immunofluorescence. Interaction of elafin with human tissue transglutaminase-2 (TG-2) was investigatedin vitro. The 33-mer peptide, a highly immunogenic gliadin peptide, was incubated with TG-2 and elafin at different concentrations. The degree of deamidation of the 33-mer peptide was analyzed by liquid chromatography-mass spectrometry. Elafin was delivered to the intestine of gluten-sensitive mice using a recombinantLactococcus lactisvector. Small intestinal barrier function, inflammation, proteolytic activity, and zonula occludens-1 (ZO-1) expression were assessed.

RESULTS: Elafin expression in the small intestinal epithelium was lower in patients with active CD compared with control patients.In vitro, elafin significantly slowed the kinetics of the deamidation of the 33-mer peptide to its more immunogenic form. Treatment of gluten-sensitive mice with elafin delivered by theL. lactisvector normalized inflammation, improved permeability, and maintained ZO-1 expression.

CONCLUSIONS: The decreased elafin expression in the small intestine of patients with active CD, the reduction of 33-mer peptide deamidation by elafin, coupled to the barrier enhancing and anti-inflammatory effects observed in gluten-sensitive mice, suggest that this molecule may have pathophysiological and therapeutic importance in gluten-related disorders.

1 Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada

2 INSERM, U1043, Toulouse, France

3 CNRS, U5282, Toulouse, France

4 Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

5 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Zürich, Switzerland

6 Commensal and Probiotics-Host Interactions Laboratory, UMR1319 Micalis, INRA, Jouy-en-Josas, France

7 Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

8 Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Buenos Aires, Argentina

Correspondence: Elena F. Verdu, MD, PhD, Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street W Hamilton, Ontario, Canada L8S 4K1. E-mail: verdue@mcmaster.ca

Received 22 November 2013; accepted 2 February 2014

published online 8 April 2014

© The American College of Gastroenterology 2014. All Rights Reserved.
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