Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity

Abstract

Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.

Nonsteroidal anti‐inflammatory drugs alleviate severity of post‐endoscopic retrograde cholangiopancreatography pancreatitis by inhibiting inflammation and reducing apoptosis

“…Commonly, cell death, including necrosis and apoptosis, occurs during acute pancreatitis and differs between different types of pancreatitis . As previous studies have indicated that acinar cell necrosis is commonly seen in severe acute pancreatitis, we decided to detect acinar cell apoptosis under less severe condition and found that acinar cell apoptosis was prevalent during PEP but was inhibited by the administration of NSAIDs. As inflammatory cytokines such as TNF‐α have been reported to be linked to increased cell apoptosis, we speculated that this phenomenon might result from decreases in inflammatory cytokines by NSAID delivery to some extent.…”

Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers to TRAIL-Induced Apoptosis via Inhibition of XIAP/NF-κB and Activation of Caspases and Death Receptor 4

“…There are accumulating evidences that XIAP, one of the IAP family members, contains a C-terminal RING domain and three distinct baculovirus IAP repeat (BIR) domains [ 23 , 24 ] and plays a critical role in NF-κB activation [ 25 ]. The BIR1/TAB1 interaction is crucial for XIAP-induced TAK1 and NF-κB (RelA/p65 and p50 subunits) activation, since the BIR2 domain of XIAP directly blocks the active sites of caspase-3 and caspase-7, while the BIR1 domain directly binds to TAB1 [ 25 , 26 , 27 ]. The NF-κB activation of XIAP is essential for cancer cell survival [ 25 ].…”

Adenovirus-mediated artificial miRNA targetting fibrinogen-like protein 2 attenuates the severity of acute pancreatitis in mice

“…However, apoptosis of acinar cells would reduce the release and activity of trypsin and ameliorate inflammation cascade. Hence, it is generally accepted that shifting death responses from necrosis to apoptosis has a therapeutic implication [ 1 , 20 , 21 ].…”

“…Severe acute pancreatitis (SAP) is a potentially fatal pathogenic condition characterized by rapid progression and high mortality [ 1 ], but the underlying pathophysiological mechanisms remain incompletely defined. The death of pancreatic acinar cell is the major pathophysiological change in early onset of acute pancreatitis, and the modalities of cell death generally contain necrosis and apoptosis [ 1 – 3 ]. The damage of pancreatic acinar cells during SAP is usually through the interaction of apoptosis and necrosis [ 2 ].…”