title: 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: 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.
authors.affiliation: Departments of Cell, Developmental, and Integrative Biology (X.L., T.A., S.R.), Pathology (R.N.B.), Microbiology (H.M.T.), and Comprehensive Diabetes Center (X.L., R.N.B., T.A., H.M.T., S.R.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Medicine (S.Z., A.B.), Mass Spectrometry Resource and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, Missouri 63110; and Department of Pharmacology and Experimental Neuroscience (K.R.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Lei
authors.forename: Robert N
authors.initials: RN
authors.lastname: Bone
authors.forename: Tomader
authors.initials: T
authors.lastname: Ali
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Alan
authors.initials: A
authors.lastname: Bohrer
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.forename: Keshore R
authors.initials: KR
authors.lastname: Bidasee
authors.forename: Sasanka
authors.initials: S
authors.lastname: Ramanadham
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D051780:Sterol Regulatory Element Binding Protein 1; D007371:Interferon-gamma; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human