| First Author | Lei X | Year | 2014 |
| Journal | Endocrinology | Volume | 155 |
| Issue | 9 | Pages | 3352-64 |
| PubMed ID | 25004092 | Mgi Jnum | J:218128 |
| Mgi Id | MGI:5616700 | Doi | 10.1210/en.2013-2134 |
| Citation | Lei X, et al. (2014) Evidence of contribution of iPLA2beta-mediated events during islet beta-cell apoptosis due to proinflammatory cytokines suggests a role for iPLA2beta in T1D development. Endocrinology 155(9):3352-64 |
| abstractText | 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 Ca(2+)-independent phospholipase A2beta (iPLA2beta) participates in ER stress-induced beta-cell apoptosis. In view of reports of elevated iPLA2beta in T1D, we examined if iPLA2beta participates in cytokine-mediated islet beta-cell apoptosis. We find that the proinflammatory cytokine combination IL-1beta+IFNgamma, induces: a) ER stress, mSREBP-1, and iPLA2beta, 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 iPLA2beta gene raises the possibility that activation of SREBP-1 after proinflammatory cytokine exposure contributes to iPLA2beta induction. The IL-1beta+IFNgamma-induced outcomes (b-g) are all inhibited by iPLA2beta inactivation, suggesting that iPLA2beta-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-iPLA2beta-Tg mice and blunted in islets from iPLA2beta-KO mice. These observations suggest that iPLA2beta-mediated events participate in amplifying beta-cell apoptosis due to proinflammatory cytokines and also that iPLA2beta activation may have a reciprocal impact on ER stress development. They raise the possibility that iPLA2beta 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. |
