Inhibition of Ca2+-Independent Phospholipase A2β (iPLA2β) Ameliorates Islet Infiltration and Incidence of Diabetes in NOD Mice

Autoimmune β-cell death leads to type 1 diabetes, and with findings that Ca 2+ -independent phospholipase A 2 β (iPLA 2 β) activation contributes to β-cell death, we assessed the effects of iPLA 2 β inhibition on diabetes development. Administration of FKGK18, a reversible iPLA 2 β 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 iPLA 2 β-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 iPLA 2 β-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA 2 β may be beneficial in ameliorating autoimmune destruction of β-cells and mitigating type 1 diabetes development.