Evidence of contribution of iPLA2β-mediated events during islet β-cell apoptosis due to proinflammatory cytokines suggests a role for iPLA2β in T1D development

Endocrinology. 2014 Sep;155(9):3352-64. doi: 10.1210/en.2013-2134. Epub 2014 Jul 8.


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 Ca(2+)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Apoptosis*
  • Cytokines / genetics
  • Cytokines / immunology*
  • Diabetes Mellitus, Type 1 / enzymology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Endoplasmic Reticulum Stress
  • Female
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / immunology*
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / immunology


  • Cytokines
  • Interleukin-1beta
  • Sterol Regulatory Element Binding Protein 1
  • Interferon-gamma
  • Group VI Phospholipases A2
  • PLA2G6 protein, human