Cross-talk between the unfolded protein response and nuclear factor-kappaB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets
AIMS/HYPOTHESIS: Pancreatic beta cell destruction in type 1 diabetes may be mediated by cytokines such as IL-1beta, IFN-gamma and TNF-alpha. Endoplasmic reticulum (ER) stress and nuclear factor-kappaB (NFkappaB) signalling are activated by cytokines, but their significance in beta cells remains unclear. Here, we investigated the role of cytokine-induced ER stress and NFkappaB signalling in beta cell destruction. METHODS: Isolated mouse islets and MIN6 beta cells were incubated with IL-1beta, 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. RESULTS: We found in beta cells that inhibition of cytokine-induced ER stress with PBA unexpectedly potentiated cell death and NFkappaB-regulated gene expression. These responses were dependent on NFkappaB activation and were associated with a prolonged decrease in the inhibitor of kappaB-alpha (IkappaBalpha) protein, resulting from increased IkappaBalpha protein degradation. Cytokine-mediated NFkappaB-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. CONCLUSIONS/INTERPRETATION: These data suggest a novel mechanism by which cytokine-mediated ER stress interacts with NFkappaB signalling in beta cells, by regulating IkappaBalpha degradation. The cross-talk between the UPR and NFkappaB signalling pathways may be important in the regulation of cytokine-mediated beta cell death.
|Authors||Chan, J. Y.; Biden, T. J.; Laybutt, D. R.|
|Responsible Garvan Author|
|Publisher Name||CELL DEATH AND DIFFERENTIATION|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22893028|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11350|