title: Inhibition of Ca2+-independent phospholipase A2β (iPLA2β) ameliorates islet infiltration and incidence of diabetes in NOD mice.
abstract: Autoimmune β-cell death leads to type 1 diabetes, and with findings that Ca(2+)-independent phospholipase A2β (iPLA2β) activation contributes to β-cell death, we assessed the effects of iPLA2β inhibition on diabetes development. Administration of FKGK18, a reversible iPLA2β inhibitor, to NOD female mice significantly reduced diabetes incidence in association with 1) reduced insulitis, reflected by reductions in CD4(+) T cells and B cells; 2) improved glucose homeostasis; 3) higher circulating insulin; and 4) β-cell preservation. Furthermore, FKGK18 inhibited production of tumor necrosis factor-α (TNF-α) from CD4(+) T cells and antibodies from B cells, suggesting modulation of immune cell responses by iPLA2β-derived products. Consistent with this, 1) adoptive transfer of diabetes by CD4(+) T cells to immunodeficient and diabetes-resistant NOD.scid mice was mitigated by FKGK18 pretreatment and 2) TNF-α production from CD4(+) T cells was reduced by inhibitors of cyclooxygenase and 12-lipoxygenase, which metabolize arachidonic acid to generate bioactive inflammatory eicosanoids. However, adoptive transfer of diabetes was not prevented when mice were administered FKGK18-pretreated T cells or when FKGK18 administration was initiated with T-cell transfer. The present observations suggest that iPLA2β-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA2β may be beneficial in ameliorating autoimmune destruction of β-cells and mitigating type 1 diabetes development.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Bone
authors.affiliation: Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gai
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Athens, Greece.
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Athens, Greece.
authors.forename: Maroula G
authors.initials: MG
authors.lastname: Kokotou
authors.affiliation: Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Tomader
authors.initials: T
authors.lastname: Ali
authors.affiliation: Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Lei
authors.affiliation: Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.affiliation: Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL sramvem@uab.edu.
authors.forename: Sasanka
authors.initials: S
authors.lastname: Ramanadham
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D001682:Biological Availability; D015496:CD4-Positive T-Lymphocytes; D002118:Calcium / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms
chemical_list: C587596:1,1,1-trifluoro-6-(naphthalen-2-yl)hexan-2-one; D007328:Insulin; D007659:Ketones; D009281:Naphthalenes; D020033:Protein Isoforms; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D005947:Glucose; D002118:Calcium