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Genetic inhibition of protein kinase C? attenuates necrosis in experimental pancreatitis.

ABSTRACT: Understanding the regulation of death pathways, necrosis and apoptosis, in pancreatitis is important for developing therapies directed to the molecular pathogenesis of the disease. Protein kinase C? (PKC?) has been previously shown to regulate inflammatory responses and zymogen activation in pancreatitis. Furthermore, we demonstrated that ethanol specifically activated PKC? in pancreatic acinar cells and that PKC? mediated the sensitizing effects of ethanol on inflammatory response in pancreatitis. Here we investigated the role of PKC? in the regulation of death pathways in pancreatitis. We found that genetic deletion of PKC? resulted in decreased necrosis and severity in the in vivo cerulein-induced pancreatitis and that inhibition of PKC? protected the acinar cells from CCK-8 hyperstimulation-induced necrosis and ATP reduction. These findings were associated with upregulation of mitochondrial Bak and Bcl-2/Bcl-xL, proapoptotic and prosurvival members in the Bcl-2 family, respectively, as well as increased mitochondrial cytochrome c release, caspase activation, and apoptosis in pancreatitis in PKC? knockout mice. We further confirmed that cerulein pancreatitis induced a dramatic mitochondrial translocation of PKC?, suggesting that PKC? regulated necrosis in pancreatitis via mechanisms involving mitochondria. Finally, we showed that PKC? deletion downregulated inhibitors of apoptosis proteins, c-IAP2, survivin, and c-FLIPs while promoting cleavage/inactivation of receptor-interacting protein kinase (RIP). Taken together, our findings provide evidence that PKC? activation during pancreatitis promotes necrosis through mechanisms involving mitochondrial proapoptotic and prosurvival Bcl-2 family proteins and upregulation of nonmitochondrial pathways that inhibit caspase activation and RIP cleavage/inactivation. Thus PKC? is a potential target for prevention and/or treatment of acute pancreatitis.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4154116 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Genetic inhibition of protein kinase Cε attenuates necrosis in experimental pancreatitis.

Liu Yannan Y Yuan Jingzhen J Tan Tanya T Jia Wenzhuo W Lugea Aurelia A Mareninova Olga O Waldron Richard T RT Pandol Stephen J SJ

American journal of physiology. Gastrointestinal and liver physiology 20140717 5

Understanding the regulation of death pathways, necrosis and apoptosis, in pancreatitis is important for developing therapies directed to the molecular pathogenesis of the disease. Protein kinase Cε (PKCε) has been previously shown to regulate inflammatory responses and zymogen activation in pancreatitis. Furthermore, we demonstrated that ethanol specifically activated PKCε in pancreatic acinar cells and that PKCε mediated the sensitizing effects of ethanol on inflammatory response in pancreatit ...[more]

PMID: 25035113

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Project description:Acinar cells in pancreatitis die through apoptosis and necrosis, the roles of which are different. The severity of experimental pancreatitis correlates directly with the extent of necrosis and inversely, with apoptosis. Apoptosis is mediated by the release of cytochrome c into the cytosol followed by caspase activation, whereas necrosis is associated with the mitochondrial membrane potential (DeltaPsim) loss leading to ATP depletion. Here, we investigate the role of Bcl-2 proteins in apoptosis and necrosis in pancreatitis. We found up-regulation of prosurvival Bcl-2 proteins in pancreas in various experimental models of acute pancreatitis, most pronounced for Bcl-xL. This up-regulation translated into increased levels of Bcl-xL and Bcl-2 in pancreatic mitochondria. Bcl-xL/Bcl-2 inhibitors induced DeltaPsim loss and cytochrome c release in isolated mitochondria. Corroborating the results on mitochondria, Bcl-xL/Bcl-2 inhibitors induced DeltaPsim loss, ATP depletion and necrosis in pancreatic acinar cells, both untreated and hyperstimulated with CCK-8 (in vitro pancreatitis model). Together Bcl-xL/Bcl-2 inhibitors and CCK induced more necrosis than either treatment alone. Bcl-xL/Bcl-2 inhibitors also stimulated cytochrome c release in acinar cells leading to caspase-3 activation and apoptosis. However, different from their effect on pronecrotic signals, the stimulation by Bcl-xL/Bcl-2 inhibitors of apoptotic responses was less in CCK-treated than control cells. Therefore, Bcl-xL/Bcl-2 inhibitors potentiated CCK-induced necrosis but not apoptosis. Correspondingly, transfection with Bcl-xL siRNA stimulated necrosis but not apoptosis in the in vitro pancreatitis model. Further, in animal models of pancreatitis Bcl-xL up-regulation inversely correlated with necrosis, but not apoptosis. Results indicate that Bcl-xL and Bcl-2 protect acinar cells from necrosis in pancreatitis by stabilizing mitochondria against death signals. We conclude that Bcl-xL/Bcl-2 inhibition would aggravate acute pancreatitis, whereas Bcl-xL/Bcl-2 up-regulation presents a strategy to prevent or attenuate necrosis in pancreatitis.

Dataset Information

Genetic inhibition of protein kinase C? attenuates necrosis in experimental pancreatitis.

Publications

Genetic inhibition of protein kinase Cε attenuates necrosis in experimental pancreatitis.

Similar Datasets

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