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

Autoimmune beta-cell death leads to type 1 diabetes, and with findings that Ca2+-independent phospholipase A(2)beta (iPLA(2)beta) activation contributes to beta-cell death, we assessed the effects of iPLA(2)beta inhibition on diabetes development. Administration of FKGK18, a reversible iPLA(2)beta 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) beta-cell preservation. Furthermore, FKGK18 inhibited production of tumor necrosis factor-alpha (TNF-alpha) from CD4+ T cells and antibodies from B cells, suggesting modulation of immune cell responses by iPLA(2)beta-derived products. Consistent with this, 1) adoptive transfer of diabetes by CD4+ T cells to immunodeficient and diabetesresistant NOD.scid mice was mitigated by FKGK18 pretreatment and 2) TNF-alpha 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)beta-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA(2)beta may be beneficial in ameliorating autoimmune destruction of I3-cells and mitigating type 1 diabetes development.