Cleavage of Protein Kinase C δ by Caspase-3 Mediates Pro-inflammatory Cytokine-Induced Apoptosis in the Pancreatic Islet

Abstract

SummaryIn type 1 diabetes (T1D), autoreactive immune cells infiltrate the pancreas and secrete pro-inflammatory cytokines that initiate cell death in insulin producing islet β-cells. Protein kinase C δ (PKCδ) plays a role in mediating cytokine-induced β-cell death; however, the exact mechanisms are not well understood. Here we explored the role of PKCδ in mediating pro-inflammatory cytokine-induced apoptosis in both mouse and human islets. Our results support a role for PKCδ activity in mediating cytokine-induced apoptosis and inhibiting PKCδ with a cell permeable inhibitor, δV1-1, also protected against cytokine-induced apoptosis in mouse and human islets. Pro-inflammatory cytokines increased PKCδ activity and nuclear translocation, and caspase-3 cleavage of PKCδ was required for cytokine-induced apoptosis. Our results support a role for PKCδ in regulation of pro-apoptotic signaling in pancreatic islets and suggest PKCδ may play a role in mediating cytokine-induced apoptosis in pancreatic β-cells in T1D.