Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69

摘要: OBJECTIVES— Non-obese diabetic (NOD) mice develop spontaneous type 1 diabetes. We have shown that sphingosine-1-phosphate (S1P) reduces activation of NOD endothelium via the S1P1 receptor. In current study, we tested hypothesis S1P could inhibit CD4 + T-cell activation, further reducing inflammatory events associated with RESEARCH DESIGN AND METHODS— T-cells were isolated from and nondiabetic mouse splenocytes treated in absence or presence receptor-specific agonist, SEW2871. Lymphocyte was examined using flow cytometry, cytokine bead assays, a lymphocyte:endothelial adhesion assay. RESULTS— Diabetic secreted twofold more γ-interferon (IFN-γ) interleukin-17 than lymphocytes. Pretreatment either SEW2871 significantly reduced secretion by ∼50%. Flow cytometry analysis showed increased expression CD69, marker lymphocyte on T-cells. Both prevented upregulation CD69 cells. Quantitative RT-PCR lymphocytes had 2.5-fold lower hypoxia-inducible factor (HIF)-1α short isoform I.1 (HIF1αI.1) mRNA levels control. HIF1αI.1 is negative regulator activation. HIF1α both control groups. IFN-γ production surface HIF1αI.1-deficient mice. did not reduce CONCLUSIONS— acts through receptor to negatively regulate providing potential therapeutic target for prevention diabetes its vascular complications.