title: Extracellular cleavage of E-cadherin by leukocyte elastase during acute experimental pancreatitis in rats.
abstract: OBJECTIVE
  Cadherins play an important role in cell-cell contact formation at adherens junctions. During the course of acute pancreatitis, adherens junctions are known to dissociate-a requirement for the interstitial accumulation of fluid and inflammatory cells-but the underlying mechanism is unknown.
  
  
  METHODS
  Acute pancreatitis was induced in rats by supramaximal cerulein infusion. The pancreas and lungs were either homogenized for protein analysis or fixed for morphology. Protein sequencing was used to identify proteolytic cleavage sites and freshly prepared acini for ex vivo studies with recombinant proteases. Results were confirmed in vivo by treating experimental pancreatitis animals with specific protease inhibitors.
  
  
  RESULTS
  A 15-kilodalton smaller variant of E-cadherin was detected in the pancreas within 60 minutes of pancreatitis, was found to be the product of E-cadherin cleavage at amino acid 394 in the extracellular domain that controls cell-contact formation, and was consistent with E-cadherin cleavage by leukocyte elastase. Employing cell culture and ex vivo acini leukocyte elastase was confirmed to cleave E-cadherin at the identified position, followed by dissociation of cell contacts and the internalization of cleaved E-cadherin to the cytosol. Inhibition of leukocyte elastase in vivo prevented E-cadherin cleavage during pancreatitis and reduced leukocyte transmigration into the pancreas.
  
  
  CONCLUSIONS
  These data provide evidence that polymorphonuclear leukocyte elastase is involved in, and required for, the dissociation of cell-cell contacts at adherens junctions, the extracellular cleavage of E-cadherin, and, ultimately, the transmigration of leukocytes into the epithelial tissue during the initial phase of experimental pancreatitis.
authors.affiliation: Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt-Universität Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schnekenburger
authors.forename: Burkhard
authors.initials: B
authors.lastname: Krüger
authors.forename: Josef
authors.initials: J
authors.lastname: Kellermann
authors.forename: Manuel
authors.initials: M
authors.lastname: Ruthenbürger
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.forename: Angel
authors.initials: A
authors.lastname: Nalli
authors.forename: Wolfram
authors.initials: W
authors.lastname: Domschke
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
mesh_terms: D000208:Acute Disease; D000818:Animals; D015820:Cadherins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D014644:Genetic Variation; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D010195:Pancreatitis / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015820:Cadherins; D011480:Protease Inhibitors; D019272:Leukocyte Elastase