The inflammatory response during
pancreatitis regulates necrotic and apoptotic rates of parenchymal cells. Neutrophil depletion by use of anti-polymorphonuclear serum (anti-PMN) increases apoptosis in experimental
pancreatitis but the mechanism has not been determined. Our study was designed to investigate signaling mechanisms in pancreatic parenchymal cells regulating death responses with neutrophil depletion. Rats were neutrophil depleted with anti-PMN treatment. Then
cerulein pancreatitis was induced, followed by measurements of apoptosis signaling pathways. There was greater activation of executioner caspases-3 in the pancreas with anti-PMN treatment compared with control. There were no differences between these groups of animals in mitochondrial
cytochrome c release or in activities of initiator
caspase-8 and -9. However, there was greater activation of
caspase-2 with anti-PMN treatment during
cerulein pancreatitis. The upstream regulation of caspases-2 includes p53, which was increased; the p53 negative regulator, Mdm2, was decreased by anti-PMN treatment during
cerulein pancreatitis. In vitro experiments using isolated pancreatic acinar cells a pharmacological inhibitor of Mdm2 increased
caspase-2/-3 activities, and an inhibitor of p53 decreased these activities during cholecystokinin-8 treatment. Furthermore, experiments using the AR42J cell line Mdm2
small interfering RNA (
siRNA) increased
caspase-2/-3 activities, and p53
siRNA decreased these activities during cholecystokinin-8 treatment. These results suggest that during
acute pancreatitis the inflammatory response inhibits apoptosis. The mechanism of this inhibition involves
caspase-2 and its upstream regulation by p53 and Mdm2. Because previous findings indicate that promotion of apoptosis decreases
necrosis and severity of
pancreatitis, these results suggest that strategies to inhibit Mdm2 or activate p53 will have beneficial effects for treatment of
pancreatitis.