CNTF protects MIN6 cells against apoptosis induced by Alloxan and IL-1β through downregulation of the AMPK pathway

Our group previously demonstrated that CNTF protects pancreatic islets against apoptosis induced by IL1 beta. In addition, it is known that AMPK knockout protects beta cells from IL1 beta-mediated apoptosis, however how AMPK activation leads to apoptosis remains unknown. The present study was designed to investigate the possible role of AMPK pathway modulation in CNTF protective effects against apoptosis induced by IL1 beta or Alloxan and how AMPK activation leads to beta cells apoptosis. First, we observed that apoptosis of MIN6 cells, induced by Alloxan as well as IL-1 beta, requires activation of the AMPK pathway, and also that CNTF protective effects are dependent on downregulation of AMPK. In addition, we found that Alloxan induces AMPK differently from IL1 beta, as Alloxan acts mainly through CaMKII while IL1 beta acts through LKB1 phosphorylation. Meanwhile, CNTF by itself inhibited the AMPK pathway and protected against AMPK activation induced by Alloxan or IL1 beta via downregulation of CaMKII. Finally, AMPK-dependent MING cell apoptosis, induced by IL1 beta or Alloxan, required increased iNOS expression, an effect that was reversed by CNTF downregulation of AMPK pathway and iNOS expression. In conclusion, IL1 beta upregulates the LKB1-AMPK-INOS pathway, while Alloxan acts through CaMKII-AMPK-INOS. both ultimately leading to beta cell death. In this context. CNTF protects beta cells against apoptosis, induced by either IL1 beta or Alloxan, through downregulation of the CaMKII-AMPK-INOS pathway. (C) 2011 Elsevier Inc. All rights reserved.