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

• Published in: Endocrinology (Philadelphia) 2014-09, Vol.155 (9), p.3352-3364
• Main Authors: Lei, Xiaoyong, Bone, Robert N, Ali, Tomader, Zhang, Sheng, Bohrer, Alan, Tse, Hubert M, Bidasee, Keshore R, Ramanadham, Sasanka
• Format: Article
• Language: English
• Subjects: Adult; Animals; Apoptosis; Beta cells; Calcium ions; Calcium signalling; Caspase-3; Cell activation; Cell death; Chemotaxis; Cytokines; Cytokines - genetics; Cytokines - immunology; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - enzymology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes-Insulin-Glucagon-Gastrointestinal; Endoplasmic Reticulum Stress; Female; Group VI Phospholipases A2 - genetics; Group VI Phospholipases A2 - immunology; Humans; IL-1β; Immune response; Immune system; Inactivation; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Islets of Langerhans - cytology; Islets of Langerhans - enzymology; Islets of Langerhans - immunology; Lipids; Lysophosphatidylcholine; Male; Mice; Mice, Knockout; Regulatory sequences; Sphingomyelin phosphodiesterase; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - immunology; Sterol regulatory element-binding protein; γ-Interferon
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2013-2134

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.