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

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• 作者：Rupjyoti Talukdar¹ ; ^&lowast ; ; Archana Sareen^&lowast ; ; ² ; Hongyan Zhu² ; Zuobiao Yuan² ; Ajay Dixit³ ; Hassam Cheema³ ; John George³ ; Usman Barlass² ; Raghuwansh Sah⁴ ; Sushil K. Garg² ; Sulagna Banerjee³ ; Pramod Garg⁵ ; Vikas Dudeja³ ; Rajinder Dawra³ ; Ashok K. Saluja³ ; ^{asaluja@miami.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cytosolic Cathepsin B ; Apoptosis ; Necrosis ; Bid Cleavage
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：151
• 期：4
• 页码：747-758.e5
• 全文大小：2959 K

文摘

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.