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Sphingosine‐1‐Phosphate Reduces CD4+ T Lymphocyte Activation Through Regulation of Hypoxia‐inducible Factor Short Isoform I.1 and CD69
Author(s) -
Srinivasan Suseela,
Lappas Courtney,
Linden Joel,
Hedrick Catherine
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1134-b
Subject(s) - endocrinology , medicine , sphingosine 1 phosphate , cytokine , downregulation and upregulation , sphingosine , receptor , nod mice , biology , agonist , chemistry , nod , diabetes mellitus , biochemistry , gene
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 (S1P), reduces endothelial activation through activation of the S1P1 receptor. In the current study, we tested the hypothesis that S1P 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 CD3antibody, diabetic T cells secreted 2‐fold more IFNγ (control, 1500pg versus 3000 pg/mg for NOD). Pretreatment with either 1μM S1P or 1μM 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 S1P and SEW2871 prevented upregulation of CD69 on CD4 + cells. Hypoxia‐Inducible Factor (HIF)‐1α short isoform I.1 plays an important role in the regulation of TCR‐triggered cytokine secretion. HIFI.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 I.1 mRNA than control. S1P significantly increased HIF1α I.1 mRNA levels in both groups. Thus, S1P increases HIF1α I.1 expression in CD4+ T cells, thereby regulating cell activation.