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.
