Abstract
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.
Highlights
Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas which has a range of severity and causes considerable morbidity and mortality [1]
Efficient transduction (. 90%) of LV-shGRP78 in AR42J cells, 48 h after infection, was documented with enhanced green fluorescent protein (GFP) expression observed with a fluorescent microscope (Figure 1A)
Our results indicated that AR42J cells induced by cerulein alone had mild pancreatic inflammation with moderately elevated levels of amylase, lipase, tumor necrosis factor-alpha (TNF-a) and interleukin 6 (IL-6), as well as high rates of apoptosis
Summary
Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas which has a range of severity and causes considerable morbidity and mortality [1]. GRP78 is a part of the anti-apoptotic molecular cell death signaling pathway [8,9,10]. Activation of ER stress signaling concurrent with increased GRP78 was observed in an arginine induced model of severe AP [11,12]. Our previous study showed that GRP78 expression was associated with apoptosis and severity of pancreatic inflammation where in vitro models of AP induced by cerulein or cerulein plus LPS [14]. These findings indicate that the expression of GRP78 is closely related to the severity of AP. Question was raised that could GRP78 serve as an effective treating target for AP? RNAi based original study was designed to explore if inhibiting the expression of GRP78 could be beneficial for the treatment of AP
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