@article {9768, title = {Inhibition of Ca2+-independent phospholipase A2β (iPLA2β) ameliorates islet infiltration and incidence of diabetes in NOD mice}, journal = {Diabetes}, volume = {64}, number = {2}, year = {2015}, note = {Cited By :7Export Date: 18 January 2017}, pages = {541-554}, type = {Article}, abstract = {Autoimmune β-cell death leads to type 1 diabetes and with findings that Ca2+-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 non-obese diabetic (NOD) mice significantly reduced diabetes incidence in association with (a) reduced insulitis, reflected by reductions in CD4+\ T-cells and B-cells, (b) improved glucose homeostasis, (c) higher circulating insulin, and (d) β-cell preservation. Further, FKGK18 inhibited production of TNFα from CD4+\ T-cells and antibodies from B-cells, suggesting modulation of immune cell responses by iPLA2β-derived products. Consistent with this, (a) adoptive transfer of diabetes by CD4+\ T-cells to immunodeficient and diabetes-resistant NOD.scid\ mice was mitigated by FKGK18 pretreatment and (b) TNFα production from CD4+\ T-cells was reduced by inhibitors of cyclooxygenase and 12-lipooxygenase, 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 FKGK18 administration is initiated with T-cell transfer. Our 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.}, author = {Bone, R. N. and Gai, Y. and Magrioti, V. and Kokotou, M. G. and Ali, T. and Lei, X. and Tse, H. M. and Kokotos, G. and Ramanadham, S.} }