Cross-talk between the unfolded protein response and nuclear factor-κB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets

Pancreatic beta cell destruction in type 1 diabetes may be mediated by cytokines such as IL-1 beta, IFN-gamma and TNF-alpha. Endoplasmic reticulum (ER) stress and nuclear factor-kappa B (NF kappa B) signalling are activated by cytokines, but their significance in beta cells remains unclear. Here, we investigated the role of cytokine-induced ER stress and NF kappa B signalling in beta cell destruction. Isolated mouse islets and MIN6 beta cells were incubated with IL-1 beta, IFN-gamma and TNF-alpha. The chemical chaperone 4-phenylbutyric acid (PBA) was used to inhibit ER stress. Protein production and gene expression were assessed by western blot and real-time RT-PCR. We found in beta cells that inhibition of cytokine-induced ER stress with PBA unexpectedly potentiated cell death and NF kappa B-regulated gene expression. These responses were dependent on NF kappa B activation and were associated with a prolonged decrease in the inhibitor of kappa B-alpha (I kappa B alpha) protein, resulting from increased I kappa B alpha protein degradation. Cytokine-mediated NF kappa B-regulated gene expression was also potentiated after pre-induction of ER stress with thapsigargin, but not tunicamycin. Both PBA and thapsigargin treatments led to preferential upregulation of ER degradation genes over ER-resident chaperones as part of the adaptive unfolded protein response (UPR). In contrast, tunicamycin activated a balanced adaptive UPR in association with the maintenance of Xbp1 splicing. These data suggest a novel mechanism by which cytokine-mediated ER stress interacts with NF kappa B signalling in beta cells, by regulating I kappa B alpha degradation. The cross-talk between the UPR and NF kappa B signalling pathways may be important in the regulation of cytokine-mediated beta cell death.