Inhibition of Ca(2+)-Independent Phospholipase A(2)β (iPLA(2)β) 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.