{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:08:33Z","timestamp":1774645713581,"version":"3.50.1"},"reference-count":30,"publisher":"American Diabetes Association","issue":"2","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,2,1]]},"abstract":"<jats:p>OBJECTIVES\u2014Non-obese diabetic (NOD) mice develop spontaneous type 1 diabetes. We have shown that sphingosine-1-phosphate (S1P) reduces activation of NOD diabetic endothelium via the S1P1 receptor. In the current study, we tested the hypothesis that S1P could inhibit CD4+ T-cell activation, further reducing inflammatory events associated with diabetes.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014CD4+ T-cells were isolated from diabetic and nondiabetic NOD mouse splenocytes and treated in the absence or presence of S1P or the S1P1 receptor-specific agonist, SEW2871. Lymphocyte activation was examined using flow cytometry, cytokine bead assays, and a lymphocyte:endothelial adhesion assay.<\/jats:p>\n               <jats:p>RESULTS\u2014Diabetic T-cells secreted twofold more \u03b3-interferon (IFN-\u03b3) and interleukin-17 than nondiabetic lymphocytes. Pretreatment with either S1P or SEW2871 significantly reduced cytokine secretion by \u223c50%. Flow cytometry analysis showed increased expression of CD69, a marker of lymphocyte activation, on diabetic T-cells. Both S1P and SEW2871 prevented upregulation of CD69 on CD4+ cells. Quantitative RT-PCR showed that lymphocytes from diabetic NOD mice had 2.5-fold lower hypoxia-inducible factor (HIF)-1\u03b1 short isoform I.1 (HIF1\u03b1I.1) mRNA levels than control. HIF1\u03b1I.1 is a negative regulator of lymphocyte activation. S1P significantly increased HIF1\u03b1 I.1 mRNA levels in both control and diabetic groups. IFN-\u03b3 production and surface CD69 expression was significantly increased in lymphocytes of HIF1\u03b1I.1-deficient mice. S1P did not reduce either CD69 or IFN-\u03b3 expression in lymphocytes from HIF1\u03b1I.1-deficient mice.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014S1P acts through the S1P1 receptor and HIF1\u03b1 I.1 to negatively regulate T-cell activation, providing a potential therapeutic target for prevention of diabetes and its vascular complications.<\/jats:p>","DOI":"10.2337\/db07-0855","type":"journal-article","created":{"date-parts":[[2007,11,15]],"date-time":"2007-11-15T01:54:07Z","timestamp":1195091647000},"page":"484-493","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":34,"title":["Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69"],"prefix":"10.2337","volume":"57","author":[{"given":"Suseela","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David T.","family":"Bolick","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitriy","family":"Lukashev","sequence":"additional","affiliation":[{"name":"New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney","family":"Lappas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Virginia, Charlottesville, Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michail","family":"Sitkovsky","sequence":"additional","affiliation":[{"name":"New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin R.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Virginia, Charlottesville, Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine C.","family":"Hedrick","sequence":"additional","affiliation":[{"name":"Robert M. 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