Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis.
The lysosomal cysteine protease cathepsin B is thought to play a central role in intrapancreatic trypsinogen activation and the onset of experimental pancreatitis. Recent in vitro studies have suggested that this mechanism might be of pathophysiological relevance in hereditary pancreatitis, a human inborn disorder associated with mutations in the cationic trypsinogen gene. In the present study evidence is presented that cathepsin B is abundantly present in the secretory compartment of the human exocrine pancreas, as judged by immunogold electron microscopy. Moreover, pro-cathepsin B and mature cathepsin B are both secreted together with trypsinogen and active trypsin into the pancreatic juice of patients with sporadic pancreatitis or hereditary pancreatitis. Finally, cathepsin B- catalyzed activation of recombinant human cationic trypsinogen with hereditary pancreatitis-associated mutations N29I, N29T, or R122H were characterized. In contrast to a previous report, cathepsin B-mediated activation of wild type and all three mutant trypsinogen forms was essentially identical under a wide range of experimental conditions. These observations confirm the presence of active cathepsin B in the human pancreatic secretory pathway and are consistent with the notion that cathepsin B-mediated trypsinogen activation might play a pathogenic role in human pancreatitis. On the other hand, the results clearly demonstrate that hereditary pancreatitis-associated mutations do not lead to increased or decreased trypsinogen activation by cathepsin B. Therefore, mutation-dependent alterations in cathepsin B-induced trypsinogen activation are not the cause of hereditary pancreatitis.
Kukor
Zoltán
Z
Department of Physiology, University of California Los Angeles, Los Angeles, California 90095, USA.
Mayerle
Julia
J
Krüger
Burkhard
B
Tóth
Miklós
M
Steed
Paul M
PM
Halangk
Walter
W
Lerch
Markus M
MM
Sahin-Tóth
Miklós
M
D015153:Blotting, Western; D002401:Cathepsin B / Q000096:biosynthesis* / Q000378:metabolism; D002412:Cations; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010179:Pancreas / Q000378:metabolism* / Q000648:ultrastructure; D010195:Pancreatitis / Q000235:genetics* / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014362:Trypsinogen / Q000378:metabolism*
D002412:Cations; D011994:Recombinant Proteins; D014362:Trypsinogen; D002401:Cathepsin B