The Sphingosine 1-Phosphate Receptor Agonist FTY720 Potently Inhibits Regulatory T Cell Proliferation In Vitro and In Vivo

Wolf, Anna Maria; Eller, Philipp; Zeiser, Robert; Dürr, Christoph; Gerlach, Uwe; Sixt, Michael; Markut, Lydia; Gastl, Guenther; Rosenkranz, Alexander R.; Wolf, Dominik

doi:10.4049/jimmunol.0901011

Cited by 52 publications

(40 citation statements)

References 53 publications

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“…In this study, we examined whether FTY720 and FTY720-P affect the immune function of Treg cells in vitro. In contrast to Wolf et al (21), we found that FTY720 did not affect the proliferation of the CD4 + CD25 + T cells. Though the proliferation of Treg cells in the high and medium dose FTY720-P group appeared to be enhanced slightly, there was still no significant difference between three FTY720-P groups and the control group.…”

Section: Discussioncontrasting

confidence: 99%

“…Several studies found that the S1P receptor agonist FTY720 could partly affect the immune function of CD4 + CD25 + Treg cells (19,20). However, one study found that the proliferation of Treg cells was impaired significantly by FTY720 (21). In this study, we examined whether FTY720 and FTY720-P affect the immune function of Treg cells in vitro.…”

Section: Discussionmentioning

confidence: 97%

“…However, there was a study which had contradictory results about the effects of FTY720 on Treg cells (21). Therefore, this study was undertaken in order to further investigate how FTY720 affected the immune function of Treg cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

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The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

Liu

Jiang

Xiao³

et al. 2012

Int J Mol Med

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Abstract. The sphingosine-1-phosphate receptor agonist FTY720 and FTY720-P have a wide variety of fundamental functions. Many studies have demonstrated that CD4 + CD25 + regulatory T (Treg) cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Although FTY720 has also recently shown to possess an additional effect that increases the functional activity of Treg cells, the mechanism leading to the enhanced Treg activity after FTY720 treatment is still not clear. We isolated Treg cells, which were co-cultured with FTY720 or FTY720-P. The proliferation of co-cultured Treg cells was detected by the cell counting kit-8. The changes of the phenotype CD25 + and forkhead box P3 (Foxp3) + of co-cultured Treg cells were measured by flow cytometry. The levels of IL-10 and TGF-β1 in the supernatants were detected by ELISA. Cytokine mRNA expressions in co-cultured Treg cells were analyzed by real-time quantitative PCR. Mixed lymphocyte reaction assay examined the suppressive function. We found that neither FTY720 nor FTY720-P affected the proliferation of co-cultured Treg cells. The percentages of CD25 + and Foxp3 + were enhanced in the high-dose FTY720-P group. The levels of TGF-β1 in the supernatants were enhanced in the high-dose FTY720 group. Medium and high-dose FTY720-P also enhanced the levels of TGF-β1. TGF-β1 and Foxp3 mRNA expression were upregulated in the high-dose FTY720-P group. The proliferation of effector T (Teff) cells was suppressed significantly in the medium and high-dose FTY720-P group at a Treg/Teff cell ratio of 1:1. At a ratio of 1:1, the proliferation of Teff cells was also suppressed in the high-dose FTY720 group. It can be concluded that high-dose FTY720-P can enhance the immune function of co-cultured Treg cells, and that medium-dose FTY720-P and high-dose FTY720 could partly enhance the function. The reason may be attributed to enhanced levels of TGF-β1 and Foxp3. IntroductionAs a synthetic structural analog of myriocin, the sphingosine-1-phosphate (S1P) receptor agonist FTY720 can regulate a wide variety of fundamental functions including cell survival, cytoskeletal rearrangements, and cell motility (1,2). It has been shown to control some autoimmunities and allergic diseases as well as to suppress transplant rejection and graft vs. host disease (3). The drug has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (4). Once FTY720 is phosphorylated in vivo by sphingosine kinase 2 (SphK2), the phosphorylated compound (FTY720-P) acts as an agonist on 4 of the 5 known S1P receptors (S1P1, S1P3, S1P4 and S1P5) (5). In contrast to classical immunosuppressants, such as cyclosporine A or FK506, FTY720 does not impair antigen-driven T-cell activation and does not interfere with T-cell proliferation at therapeutically relevant concentrations, but induces a severe deprivation in lymphocytes in the blood due to modification of S1P signaling (6-8).Regulatory T (Treg) cells have been demonstrated to engage in the main...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 97%

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The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

Liu

Jiang

Xiao³

et al. 2012

Int J Mol Med

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“…FTY720 modulates S1P signaling, preventing lymphocyte egress from the thymus and spleen into the blood and from the lymph nodes (LNs) into the lymph, thus blocking lymphocyte trafficking to target tissues (5,6). It also affects dendritic cell (DC) migration (16,31), modulates DC proinflammatory signaling, and is a potent inhibitor of regulatory T cell (Treg) proliferation (56). Controversy surrounds the complex mechanism of action of FTY720 in vivo, and it is unclear whether it acts as an agonist, a functional antagonist, or both during the regulation of lymphocyte recirculation (21,47,52,58).…”

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confidence: 99%

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

et al. 2012

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The sphingosine-1-phosphate (S1P) analogue FTY720 is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents the migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, mesenteric lymph nodes (MLNs), and Peyer's patches. However, evidence suggests that its clinical use may increase the risk of mucosal infections. We investigated the impact of FTY720 treatment on susceptibility to gastrointestinal infection with the mouse enteric pathogen Citrobacter rodentium. This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice that resembles human infection with pathogenic Escherichia coli. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs, and prevented the clearance of bacteria when mice were infected with luciferase-tagged C. rodentium. FTY720-treated C. rodentium-infected mice had enhanced colonic inflammation, with significantly higher colon mass, colon histopathology, and neutrophil infiltration than vehicle-infected animals. In addition, FTY720-treated infected mice had significantly lower numbers of colonic dendritic cells, macrophages, and T cells. Gene expression analysis demonstrated that FTY720-treated infected mice had an impaired innate immune response and a blunted mucosal adaptive immune response, including Th1 cytokines. The data demonstrate that the S1P analogue FTY720 adversely affects the immune response to and clearance of C. rodentium.

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“…The expression of receptors for S1P in Th1 and Th2 cells has also been reported [101,102]. S1P 1 , S1P 3 , S1P 4 , and S1P 5 were found to be expressed in both cell types.…”

Section: Effects On T Cellsmentioning

confidence: 62%

Effects of Lysophospholipids on Tumor Microenvironment

Rolin

Maghazachi

2011

Cancer Microenvironment

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The effects of lysophospholipids (LPLs) on cancer microenvironment is a vast and growing field. These lipids are secreted physiologically by various cell types. They play highly important roles in the development, activation and regulation of the immune system. They are also secreted by cancerous cells and there is a strong association between LPLs and cancer. It is clear that these lipids and in particular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) play major roles in regulating the growth of tumor cells, and in manipulating the immune system. These activities can be divided into two parts; the first involves the ability of S1P and LPA to either directly or through some of the enzymes that generate them such as sphingosine kinases or phospholipases, induce the motility and invasiveness of tumor cells. The second mechanism involves the recently discovered effects of these lipids on the anti-tumor effector natural killer (NK) cells. Whereas S1P and LPA induce the recruitment of these effector cells, they also inhibit their cytolysis of tumor cells. This may support the environment of cancer and the ability of cancer cells to grow, spread and metastasize. Consequently, LPLs or their receptors may be attractive targets for developing drugs in the treatment of cancer where LPLs or their receptors are up-regulated.

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The Sphingosine 1-Phosphate Receptor Agonist FTY720 Potently Inhibits Regulatory T Cell Proliferation In Vitro and In Vivo

Cited by 52 publications

References 53 publications

The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

Effects of Lysophospholipids on Tumor Microenvironment

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