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