Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis

Rupjyoti Talukdar, Archana Sareen, Hongyan Zhu, Zuobiao Yuan, Ajay Dixit, Hassam Cheema, John George, Usman Barlass, Raghuwansh Sah, Sushil K. Garg, Sulagna Banerjee, Pramod Garg, Vikas Dudeja, Rajinder Dawra, Ashok K. Saluja

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29 Scopus citations

Abstract

Background & Aims Experimental studies in acute pancreatitis (AP) suggest a strong association of acinar cell injury with cathepsin B–dependent intracellular activation of trypsin. However, the molecular events subsequent to trypsin activation and their role, if any, in cell death is not clear. In this study, we have explored intra-acinar events downstream of trypsin activation that lead to acinar cell death. Methods Acinar cells prepared from the pancreas of rats or mice (wild-type, trypsinogen 7, or cathepsin B–deleted) were stimulated with supramaximal cerulein, and the cytosolic activity of cathepsin B and trypsin was evaluated. Permeabilized acini were used to understand the differential role of cytosolic trypsin vs cytosolic cathepsin B in activation of apoptosis. Cell death was evaluated by measuring specific markers for apoptosis and necrosis. Results Both in vitro and in vivo studies have suggested that during AP cathepsin B leaks into the cytosol from co-localized organelles, through a mechanism dependent on active trypsin. Cytosolic cathepsin B but not trypsin activates the intrinsic pathway of apoptosis through cleavage of bid and activation of bax. Finally, excessive release of cathepsin B into the cytosol can lead to cell death through necrosis. Conclusions This report defines the role of trypsin in AP and shows that cytosolic cathepsin B but not trypsin activates cell death pathways. This report also suggests that trypsin is a requisite for AP only because it causes release of cathepsin B into the cytosol.

Original languageEnglish (US)
Pages (from-to)747-758.e5
JournalGastroenterology
Volume151
Issue number4
DOIs
StatePublished - Oct 1 2016

Keywords

  • Apoptosis
  • Bid Cleavage
  • Cytosolic Cathepsin B
  • Necrosis

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    Talukdar, R., Sareen, A., Zhu, H., Yuan, Z., Dixit, A., Cheema, H., George, J., Barlass, U., Sah, R., Garg, S. K., Banerjee, S., Garg, P., Dudeja, V., Dawra, R., & Saluja, A. K. (2016). Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis. Gastroenterology, 151(4), 747-758.e5. https://doi.org/10.1053/j.gastro.2016.06.042