FTY720 stimulates multidrug transporter– and cysteinyl leukotriene–dependent T cell chemotaxis to lymph nodes

Abstract

IntroductionFTY720 is a synthetic sphingosine immunosuppressant that prolongs the survival of allografts without impairing normal T and B cell activation (1). In vitro studies have proposed that FTY720, like other sphingosine derivatives, may cause apoptotic death of the T cell, although the concentrations needed for this effect are greater than the normal therapeutic dose (2). FTY720 may also prolong graft survival by decreasing T cell infiltration into allografts or otherwise altering normal T cell trafficking. Recent studies demonstrate the disappearance of lymphocytes, especially T cells, from peripheral blood and spleen within 3-24 hours after a single oral dose of the drug. Concurrently, there is a marked increase in the number of lymphocytes in peripheral LNs, mesenteric LNs, and Peyer's patches (3). The LN sequestration of lymphocytes may be involved in the immunosuppressive effects of FTY720, as regulated trafficking of lymphocytes is necessary for systemic immune responses and allograft rejection (4, 5).A recent report demonstrates that FTY720 becomes phosphorylated in vivo and then acts as a potent agonist for multiple sphingosine-1-phosphate (S1P) receptors (S1PRs) (6). S1PR activation seems responsible for downstream events that lead to lymphocyte homing. However, the cellular and molecular mechanisms are not understood. Recent studies demonstrate a novel role for lipid mediators in LN homing of DCs. A blind screening of neutralizing mAb's led to the discovery that the lipid transporter ABCB1 (previously called MDR-1 and P-glycoprotein; for new nomenclature, see http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html) regulates human DC migration to afferent lymphatics (7). Coupled with the hydrolysis of ATP, ABCB1 transports a wide range of compounds with various structures and targets, including ceramide analogs (8) and platelet-activating factor (9, 10), from the cytosol to the extracellular environment. A subsequent study demonstrated a role for another lipid transporter, Abcc1 (previously called Mrp1), in the migration of DCs to lymphatics. Abcc1 physiologically transports sphingolipid analogs and cysteinyl leukotriene C 4 (LTC 4 ), which is metabolized in the extracellular environment to LTD 4 and LTE 4 (11, 12). Mice lacking the Abcc1 gene show markedly decreased migration of Langerhans cells to LNs. Administration of exogenous cysteinyl leukotrienes (cysLTs) restores DC migration in these mice (13). These studies also demonstrate that both transporters are required for human DC migratory activity. However, whether the two transporters function in an interactive manner remains unclear (13,14).The mechanism by which Abcc1 causes LN homing of DCs was further shown to be chemokine-mediated. FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes T cell homing from spleen and peripheral blood to LNs by acting as an agonist for sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances the activity of the sphingosine transporter Abcb1 (Mdr1) and ...

The immunosuppressant FTY720 down‐regulates sphingosine 1‐phosphate G protein‐coupled receptors

“…A recent study demonstrates that overexpressed or mutated proteins of the ubiquitin protein degradation pathway are capable of reversing FTY720-induced growth inhibition in yeast (40). Drug transporters have also been proposed to play a role in FTY720-induced immunosuppression (41).…”

P-glycoprotein Dysfunction Contributes to Hepatic Steatosis and Obesity in Mice

“…On the basis of its ability to transport a large range of lipids [8], [9], a role in lipid homeostasis has been evocated for Pgp but has never been clearly established in vivo .…”

Expression of 5‐lipoxygenase (5‐LOX) in T lymphocytes

“…33 Cysteinyl LTs have been implicated in T-cell chemotaxis to lymph nodes and renal allograft rejection but studies are needed to further characterize their role in T-lymphocyte function. 59,60 Recently, degradation of 5-LOX after the splitting of BL41-E95-A cells, an Epstein-Barr-virus-infected Burkitt's lymphoma B-cell line, was strongly correlated with the activation of caspases 6 and 8. 61 This decrease in 5-LOX seemed to be necessary for cells to resume proliferation.…”