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

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