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J. Biol. Chem., Vol. 277, Issue 24, 21389-21396, June 14, 2002

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Presence of Cathepsin B in the Human Pancreatic Secretory Pathway and Its Role in Trypsinogen Activation during Hereditary Pancreatitis^*

Zoltán Kukor, Julia Mayerle^§, Burkhard Krüger^¶, Miklós Tóth, Paul M. Steed^**, Walter Halangk, Markus M. Lerch^§§§, and Miklós Sahin-Tóth^§§¶¶

From the  Department of Physiology, University of California Los Angeles, Los Angeles, California 90095, ^§ Department of Medicine B, Westfälische Wilhelms-Universität Münster, 48129 Münster, Germany, ^¶ Division of Medical Biology, Department of Pathology, Universität Rostock, 18057 Rostock, Germany,  Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary, 1088, ^** Research Department, Novartis Pharmaceuticals, Summit, New Jersey, 07901, and  Department of Surgery, Otto von Guericke-Universität, 39120 Magdeburg, Germany

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.

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