T1819 Regulation of Acute Pancreatitis By JAK-3-SMAD Signaling in Mice and Human

Abstract

G A A b st ra ct s mitochondrial membrane potential and cytochrome c release. Results: In pancreatitis, neutrophil-depletion (ND) caused increase in executioner caspase-3 activity, whereas cytochrome c release and mitochondrial functions were no affected. These results indicated that increased apoptosis was not mediated through direct effect of neutrophil-derived mediators on mitochondrial function. ND greatly increased the protein level and activity of caspase-2 which, in turn, activated downstream caspase-3 leading to apoptosis in cerulein pancreatitis. Neither levels nor activities of caspases-9 and -8 were affected. P53, a known activator of caspase2, was upregulated by ND in rats with pancreatitis, and increased p53 was associated with degradation of MDM2, a ubiquitin ligase which degrades p53. Furthermore, we showed that supramaximal CCK stimulated caspase-2 activation in rat pancreatic acinar cells, and that this activation was prevented by the p53 inhibitor, pifithrin-alpha. On the other hand, the MDM2 inhibitor, nutlin-3, potentiated CCK-induced activation of caspase-2. Conclusion: Thus, our results indicate that ND increase apoptosis in cerulein pancreatitis through MDM2 degradation leading to the upregulation of p53 which, in turn, stimulates activity of caspase2 of pancreatic parenchymal cells. The results suggest upregulation of p53 as the potential therapeutic strategies to stimulate apoptosis and decrease necrosis and severity of acute pancreatitis.