Cleavage of protein kinase c δ by caspase-3 mediates pro-inflammatory cytokine-induced apoptosis in pancreatic islets

In type 1 diabetes (T1D), autoreactive immune cells infiltrate the pancreas and secrete pro-inflammatory cytokines that initiate cell death in insulin producing islet {beta}-cells. Protein kinase C {delta} (PKC{delta}) plays a role in mediating cytokine-induced {beta}-cell death; however, the exact mechanisms are not well understood. To address this, we utilized an inducible {beta}-cell specific PKC{delta} KO mouse as well as a small peptide specific inhibitor of PKC{delta}. We identified a role for PKC{delta} in mediating cytokine-induced {beta}-cell death and have shown that inhibiting PKC{delta} protects pancreatic {beta}-cells from cytokine-induced apoptosis in both mouse and human islets. We determined that cytokines induced nuclear translocation and activity of PKC{delta} and that caspase-3 cleavage of PKC{delta} may be required for cytokine-mediated islet apoptosis. Further, cytokine-activated PKC{delta} increases activity both of pro-apoptotic Bax with acute treatment and JNK with prolonged treatment. Overall, our results suggest that PKC{delta} mediates cytokine-induced apoptosis via nuclear translocation, cleavage by caspase-3, and upregulation of pro-apoptotic signaling in pancreatic {beta}-cells. Combined with the protective effects of PKC{delta} inhibition with {delta}V1-1, the results of this study will aid in the development of novel therapies to prevent or delay {beta}-cell death and preserve {beta}-cell function in T1D.