Evidence of Contribution of iPLA2β-Mediated Events During Islet β-Cell Apoptosis Due to Proinflammatory Cytokines Suggests a Role for iPLA2β in T1D Development

Abstract

Abstract Type 1 diabetes (T1D) results from autoimmune destruction of islet β-cells, but the underlying mechanisms that contribute to this process are incompletely understood, especially the role of lipid signals generated by β-cells. Proinflammatory cytokines induce ER stress in β-cells and we previously found that the Ca2+-independent phospholipase A2β (iPLA2β) participates in ER stress-induced β-cell apoptosis. In view of reports of elevated iPLA2β in T1D, we examined if iPLA2β participates in cytokine-mediated islet β-cell apoptosis. We find that the proinflammatory cytokine combination IL-1β+IFNγ, induces: a) ER stress, mSREBP-1, and iPLA2β, b) lysophosphatidylcholine (LPC) generation, c) neutral sphingomyelinase-2 (NSMase2), d) ceramide accumulation, e) mitochondrial membrane decompensation, f) caspase-3 activation, and g) β-cell apoptosis. The presence of a sterol regulatory element in the iPLA2β gene raises the possibility that activation of SREBP-1 after proinflammatory cytokine exposure contributes to iPLA2β induction. The IL-1β+IFNγ-induced outcomes (b–g) are all inhibited by iPLA2β inactivation, suggesting that iPLA2β-derived lipid signals contribute to consequential islet β-cell death. Consistent with this possibility, ER stress and β-cell apoptosis induced by proinflammatory cytokines are exacerbated in islets from RIP-iPLA2β-Tg mice and blunted in islets from iPLA2β-KO mice. These observations suggest that iPLA2β-mediated events participate in amplifying β-cell apoptosis due to proinflammatory cytokines and also that iPLA2β activation may have a reciprocal impact on ER stress development. They raise the possibility that iPLA2β inhibition, leading to ameliorations in ER stress, apoptosis, and immune responses resulting from LPC-stimulated immune cell chemotaxis, may be beneficial in preserving β-cell mass and delaying/preventing T1D evolution.