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Sphingosine-1-Phosphate Reduces CD4 T-Cell Activation in Type 1

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Sphingosine-1-Phosphate Reduces CD4 T-Cell Activation in Type 1 ORIGINAL ARTICLE Sphingosine-1-Phosphate Reduces CD4؉ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69 Suseela Srinivasan,1 David T. Bolick,1 Dmitriy Lukashev,2 Courtney Lappas,3 Michail Sitkovsky,2 Kevin R. Lynch,3 and Catherine C. Hedrick1,3 OBJECTIVES—Non-obese diabetic (NOD) mice develop spon- taneous type 1 diabetes. We have shown that sphingosine-1- phosphate (S1P) reduces activation of NOD diabetic endothelium phingosine-1-phosphate (S1P) is a bioactive lipid via the S1P1 receptor. In the current study, we tested the hypoth- that functions as an extracellular mediator and as esis that S1P could inhibit CD4ϩ T-cell activation, further reduc- an intracellular second messenger. S1P is synthe- ing inflammatory events associated with diabetes. Ssized by a wide variety of cell types, including ϩ lymphocytes, platelets, and macrophages in response to RESEARCH DESIGN AND METHODS—CD4 T-cells were isolated from diabetic and nondiabetic NOD mouse splenocytes growth factors and cytokines (1). S1P evokes diverse and treated in the absence or presence of S1P or the S1P1 cellular responses by binding to a group of five G-protein– receptor-specific agonist, SEW2871. Lymphocyte activation was coupled receptors of the endothelial differentiation gene examined using flow cytometry, cytokine bead assays, and a (Edg) family. S1P receptor expression varies among vas- lymphocyte:endothelial adhesion assay. cular cell types, with T-cells expressing only S1P1 and S1P4 (2). Recently, we reported an anti-inflammatory role RESULTS—Diabetic T-cells secreted twofold more ␥-interferon for S1P in aortic endothelial cells, most likely through (IFN-␥) and interleukin-17 than nondiabetic lymphocytes. Pre- S1P1 action (3). Studies have recently shown that S1P treatment with either S1P or SEW2871 significantly reduced receptor agonists, such as FTY720, reduce renal (4) and ϳ cytokine secretion by 50%. Flow cytometry analysis showed hepatic ischemic injury (5). FTY720 is currently being used increased expression of CD69, a marker of lymphocyte activa- in phase III clinical trials for multiple sclerosis (6) and has tion, on diabetic T-cells. Both S1P and SEW2871 prevented ϩ been shown to prevent onset of autoimmune diabetes in upregulation of CD69 on CD4 cells. Quantitative RT-PCR showed that lymphocytes from diabetic NOD mice had 2.5-fold mouse models in vivo (7). Nofer et al. (8) have recently lower hypoxia-inducible factor (HIF)-1␣ short isoform I.1 reported that FTY720 reduces atherosclerosis in LDL (HIF1␣I.1) mRNA levels than control. HIF1␣I.1 is a negative receptor–deficient mice. Other studies have shown the regulator of lymphocyte activation. S1P significantly increased importance of S1P and the S1P1 receptor in modulating HIF1␣ I.1 mRNA levels in both control and diabetic groups. IFN-␥ T-cell proliferation and homing to lymph nodes (9,10). production and surface CD69 expression was significantly in- Furthermore, S1P has recently been shown to regulate creased in lymphocytes of HIF1␣I.1-deficient mice. S1P did not lymphocyte egress from peripheral lymph nodes through reduce either CD69 or IFN-␥ expression in lymphocytes from interaction with the adaptor protein DOCK2 (11). FTY720 HIF1␣I.1-deficient mice. and SEW2871, two well-characterized S1P receptor ago- nists that act on the S1P1 receptor, cause dramatic lym- CONCLUSIONS—S1P acts through the S1P1 receptor and ␣ phopenia in mice when used in vivo. Goetzl and colleagues HIF1 I.1 to negatively regulate T-cell activation, providing a (12,13) have shown that S1P regulates CD4ϩ T-cell che- potential therapeutic target for prevention of diabetes and its vascular complications. Diabetes 57:484–493, 2008 motaxis and proliferation through action on S1P1. Thus, S1P analogs have the potential to be important drug therapies for inflammation and immune responses in a wide range of diseases. Hypoxia-inducible factor (HIF)-1␣ is a basic helix-loop- From the 1Robert M. Berne Cardiovascular Research Center, University of helix transcription factor that is induced under hypoxic Virginia, Charlottesville, Virginia; the 2New England Inflammation and Tissue conditions. HIF1␣ can also be induced during normoxic Protection Institute, Northeastern University, Boston, Massachusetts; and the 3Department of Pharmacology, University of Virginia, Charlottesville, Virginia. conditions by vascular endothelial growth factor and other Address correspondence and reprint requests to Catherine C. Hedrick, PhD, growth factors, various lipids, thrombin, and angiotensin II Cardiovascular Research Center, University of Virginia, P.O. Box 801394, 415 (14). The murine HIF1␣ gene contains two different first Lane Rd., MR5, Rm. G123, Charlottesville, VA 22908. E-mail: cch6n@virginia. ␣ edu. exons, termed I.1 and I.2 (15). Expression of HIF1 I.1 and Received for publication 23 June 2007 and accepted in revised form 31 I.2 is regulated via two distinct promoters, which give rise October 2007. to these two mRNA isoforms (15). HIF␣I.1 is inducible and Published ahead of print at http://diabetes.diabetesjournals.org on 14 No- vember 2007. DOI: 10.2337/db07-0855. differentially expressed, whereas the longer, classical iso- ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated form, HIF1␣I.2, is constitutively expressed. The isoform cell sorting; FITC, fluorescein isothiocyanate; HIF, hypoxia-inducible factor; HIF1␣ I.1 is an immediately early response gene in T-cells HIFBS, heat-inactivated fetal bovine serum; IFN-␥, ␥-interferon; IL, interleu- that is differentially upregulated upon T-cell receptor kin; mAb, monoclonal antibody; S1P, sphingosine-1-phosphate; TCR, T-cell receptor; TNF-␣, tumor necrosis factor-␣; UVA, University of Virginia. (TCR) activation of T-cells (16). Rapid accumulation of © 2008 by the American Diabetes Association. HIF1␣I.1 in activated T-cells has been observed in vivo The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance during cytokine-mediated inflammation (16). The first in- with 18 U.S.C. Section 1734 solely to indicate this fact. dications that HIF1␣ had both immunosuppressive and 484 DIABETES, VOL. 57, FEBRUARY 2008 S. SRINIVASAN AND ASSOCIATES TABLE 1 Quantitative real-time PCR primers used in this study Name Sequence IFN-␥ Forward 5Ј-ACT CAA GTG GCA TAG ATG TGG AAG-3Ј Reverse 5Ј-GAC GCT TAT GTT GTT GCT GAT GG-3Ј IL-4 Forward 5Ј-ACA GGA GAA GGG ACG CCA TT-3Ј Reverse 5Ј-GAA GCC CTA CAG ACG AGC TCA-3Ј HIF1␣I.1 Forward 5Ј-CCC CGT CCA CCC ATT TCT-3Ј Reverse 5Ј-CTG GCT TCT TGC TTA CAG GAG AG-3Ј HIF1␣I.2 Forward 5Ј-CAC CGA TTC GCC ATG GA-3Ј Reverse 5Ј-TTT TCG ACG TTC AGA ACT CAT C-3Ј CD69 Forward 5Ј-TTC GAC GTT CAG AAC TCA TCT TTT-3Ј Reverse 5Ј-GCT GTT AAA TTC TTT GCC ATT TG-3Ј Cyclophilin Forward 5Ј-TGG AGA GCA CCA AGA CAG ACA-3Ј Reverse 5Ј-TGC CGG AGT CGA CAA TGA T-3Ј IL-17 Forward 5Ј-TCT CTG ATG CTG TTG CTG CT-3Ј Reverse 5Ј-AGG AAG TCC TTG GCC TCA GT-3Ј tissue-protective roles were provided by in vivo studies In vivo studies of SEW2871 action. Diabetic and nondiabetic NOD mice showing dramatically increased autoimmunity and tissue were bled retro-orbitally to obtain a prebleed sample. Mice were then injected damage in chimeric mice that possessed genetic deficiency intravenously with 2 mg/kg body wt SEW2871. After 4 h, blood was collected ␣ for measurement of plasma cytokine levels. Cytokines (IL-4, IL-10, and of HIF1 in their T- and B-cells (17). Direct evidence that ␥-interferon [IFN-␥]) were measured using ELISA. both isoforms of HIF1␣ are immunosuppressive in acti- CD4؉ T-cell isolation and activation. Spleens were harvested from female vated T-cells was provided by studying T-cells from mice diabetic and age-matched nondiabetic NOD mice, and the tissue was gently with complete genetic knockout of HIF1␣ isoforms (18). disrupted in PBS containing 5% heat-inactivated fetal bovine serum (HIFBS) Sitkovsky and colleagues (18) have shown that the on ice. Splenocytes were passed through a 40-␮m nylon cell strainer (BD ␣ Biosciences) and collected in PBS. Erythrocytes were removed using lysing HIF1 I.1 isoform is anti-inflammatory in T-cells, thereby ϩ preventing T-cell activation in vivo. Interactions between buffer (Sigma-Aldrich). CD4 T-cells were isolated with mouse CD4 subset column kit following the manufacturer’s protocol. The purity of CD4ϩ T-cells the immunosuppressive A2A adenosine receptor and Ͼ ␣ after isolation was 95% as measured by flow cytometry using anti-CD4 HIF1 in T-cells was first suggested by Sitkovsky and antibody. Cells were washed and resuspended in RPMI 1640 containing 10% colleagues (19,20). These studies led us to hypothesize HIFBS and 1% antibiotic-antimycotic solution. T-cells were activated in that the immunosuppressive effects of S1P could be re- 96-well plates coated with 2–10 ␮g/ml immobilized anti-CD3 mAb in the lated to HIF1␣ function in lymphocytes. presence and absence of 500 nmol/l S1P, 1 ␮mol/l S1P, or 1 ␮mol/l SEW2871 at 37°C in 5% CO for 16 h. In some studies, cells were incubated in the Despite several reports showing a protective role for 2 presence of 100 ng/ml pertussis toxin or 10 ␮mol/l VPC23019 for 16 h to inhibit S1P and S1P receptor agonists in inflammatory and im- S1P1 receptor signaling. mune diseases, the precise mechanisms for S1P action in Cytokine measurements. Splenic CD4ϩ T-cells were isolated and activated inhibiting inflammation and tissue damage are unclear. In as described above. IFN-␥, IL-4, IL-17, and IL-10 levels secreted into the media the current study, we report for the first time that S1P were measured by ELISA of cell supernatants after 16 h of treatment with 500 induces HIF1␣I.1 expression and activity to modulate nmol/l or 1 ␮mol/l S1P, 1 ␮mol/l SEW2871, or in some cases 100 ng/ml T-cell activation in NOD diabetic mice.
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