Acute pancreatitis (AP) is a potentially lethal disease characterized by
inflammation and parenchymal cell death; also, the severity of AP correlates directly with
necrosis and inversely with apoptosis. However, mechanisms of regulating cell death in AP remain unclear. The endoplasmic reticulum (ER) chaperone
protein GRP78 has anti-apoptotic properties, in addition to modulating ER stress responses. This study used RNA interference (RNAi) approach to investigate the potential role of
GRP78 in regulating apoptosis during AP. In vitro models of AP were successfully developed by treating AR42J cells with
cerulein or
cerulein plus lipoplysaccharide (LPS). There was more pancreatic
inflammation and less apoptosis with the
cerulein plus LPS treatment. Furthermore, knockdown of
GRP78 expression markedly promoted apoptosis and reduced
necrosis in pancreatic acinar cells. This was accomplished by enhancing the activation of
caspases and inhibiting the activity of
X-linked inhibitor of apoptosis protein (XIAP), as well as a receptor interacting
protein kinase-1(RIPK1), which is a key mediator of
necrosis. This attenuated the severity of pancreatic
inflammation, especially after
cerulein plus LPS treatment. In conclusion, these findings indicate that
GRP78 plays an anti-apoptotic role in regulating the cell death response during AP. Therefore,
GRP78 is a potential therapeutic target for AP.