title: Cathepsin L inactivates human trypsinogen, whereas cathepsin L-deletion reduces the severity of pancreatitis in mice.
abstract: OBJECTIVE
  Acute pancreatitis is characterized by an activation cascade of digestive enzymes in the pancreas. The first of these, trypsinogen, can be converted to active trypsin by the peptidase cathepsin B (CTSB). We investigated whether cathepsin L (CTSL) can also process trypsinogen to active trypsin and has a role in pancreatitis.
  
  
  METHODS
  In CTSL-deficient (Ctsl(-/-)) mice, pancreatitis was induced by injection of cerulein or infusion of taurocholate into the pancreatic duct. Human tissue, pancreatic juice, mouse pancreatitis specimens, and recombinant enzymes were studied by enzyme assay, immunoblot, N-terminal sequencing, immunocytochemistry, and electron microscopy analyses. Isolated acini from Ctsl(-/-) and Ctsb(-/-) mice were studied.
  
  
  RESULTS
  CTSL was expressed in human and mouse pancreas, colocalized with trypsinogen in secretory vesicles and lysosomes, and secreted into pancreatic juice. Severity of pancreatitis was reduced in Ctsl(-/-) mice, whereas apoptosis and intrapancreatic trypsin activity were increased. CTSL-induced cleavage of trypsinogen occurred 3 amino acids toward the C-terminus from the CTSB activation site and resulted in a truncated, inactive form of trypsin and an elongated propeptide (trypsinogen activation peptide [TAP]). This elongated TAP was not detected by enzyme-linked immunosorbent assay (ELISA) but was effectively converted to an immunoreactive form by CTSB. Levels of TAP thus generated by CTSB were not associated with disease severity, although this is what the TAP-ELISA is used to determine in the clinic.
  
  
  CONCLUSIONS
  CTSL inactivates trypsinogen and counteracts the ability of CTSB to form active trypsin. In mouse models of pancreatitis, absence of CTSL induces apoptosis and reduces disease severity.
authors.affiliation: Division of Experimental Surgery, Department of Surgery, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wartmann
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Thilo
authors.initials: T
authors.lastname: Kähne
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
authors.forename: Manuel
authors.initials: M
authors.lastname: Ruthenbürger
authors.forename: Rainer
authors.initials: R
authors.lastname: Matthias
authors.forename: Anne
authors.initials: A
authors.lastname: Kruse
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Weiss
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.forename: Hans
authors.initials: H
authors.lastname: Lippert
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schulz
authors.forename: Ali
authors.initials: A
authors.lastname: Aghdassi
authors.forename: Annegret
authors.initials: A
authors.lastname: Dummer
authors.forename: Steffen
authors.initials: S
authors.lastname: Teller
authors.forename: Walter
authors.initials: W
authors.lastname: Halangk
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D002108:Ceruletide / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008049:Lipase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D013656:Taurocholic Acid / Q000009:adverse effects; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism*
chemical_list: D013656:Taurocholic Acid; D002108:Ceruletide; D014362:Trypsinogen; D008049:Lipase; D000681:Amylases; D014357:Trypsin; D002401:Cathepsin B; D056668:Cathepsin L