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- Title
Sphingosine-1-Phosphate Reduces CD4+ T Lymphocyte Activation Through Regulation of Hypoxia-inducible Factor Short Isoform 1.1 and CD69.
- Authors
Srinivasan, Suseela; Lappas, Courtney; Linden, Joel; Hedrick, Catherine
- Abstract
Non obese diabetic (NOD) mice develop spontaneous Type 1 diabetes. We have shown that NOD diabetic mice have activated aortic endothelium. Further, we have found that the sphingolipid, sphingosine-1-phosphate (SIP), reduces endothelial activation through activation of the S1P1 receptor, in the current study, we tested the hypothesis that SIP could inhibit CD4+T cell activation, thereby further reducing inflammatory events associated with atherosclerosis. CD4+ T lymphocytes were isolated from diabetic NOD and control splenocytes. Upon activation via CD3 antibody, diabetic T cells secreted 2-fold more IFNγ (control, 1500pg versus 3000 pg/mg for NOD). Pretreatment with either 1µM SIP or IµM of the S1P1 receptor agonist SEW2871 significantly reduced IFNγ secretion by 40%, (*p<0.001). FACS analysis showed increased expression of CD69 in diabetic T cells. Both SIP and SEW2871 prevented upregulation of CD69 on CD4+ cells. Hypoxia-Inducible Factor (HIF)-1α short isoform 1.1 plays an important role in the regulation of TCR-triggered cytokine secretion. HIF1.1 has been shown to negatively regulate lymphocyte activation. Quantitative RT-PCR for both HIF1α isoforms showed that diabetic NOD mice had 2.5-fold lower HIF1α 1.1 mRNA than control. SIP significantly increased HIF1α 1.1 mRNA levels in both groups. Thus, SIP increases HIF1α 1.1 expression in CD4+ T cells, thereby regulating cell activation.
- Subjects
ENZYME activation; SPHINGOSINE; GENETIC regulation; DIABETES; LABORATORY mice; SPHINGOLIPIDS; INFLAMMATION
- Publication
FASEB Journal, 2007, Vol 21, Issue 6, pA1134
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.6.a1134-b