| First Author | Bone RN | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 2 | Pages | 541-54 |
| PubMed ID | 25213337 | Mgi Jnum | J:246157 |
| Mgi Id | MGI:5924763 | Doi | 10.2337/db14-0097 |
| Citation | Bone RN, et al. (2015) Inhibition of Ca2+-independent phospholipase A2beta (iPLA2beta) ameliorates islet infiltration and incidence of diabetes in NOD mice. Diabetes 64(2):541-54 |
| abstractText | Autoimmune beta-cell death leads to type 1 diabetes, and with findings that Ca(2+)-independent phospholipase A2beta (iPLA2beta) activation contributes to beta-cell death, we assessed the effects of iPLA2beta inhibition on diabetes development. Administration of FKGK18, a reversible iPLA2beta 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 iPLA2beta-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-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 iPLA2beta-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA2beta may be beneficial in ameliorating autoimmune destruction of beta-cells and mitigating type 1 diabetes development. |
