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

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Print ISSN: 0021-9738 (Print) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE

Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.

Lysophospholipids* ; Receptors, G-Protein-Coupled*; ATP Binding Cassette Transporter, Subfamily B, Member 1/*physiology ; Chemotaxis, Leukocyte/*drug effects ; Cysteine/*physiology ; Immunosuppressive Agents/*pharmacology ; Leukotrienes/*physiology ; Lymph Nodes/*immunology ; Multidrug Resistance-Associated Proteins/*physiology ; Sphingosine/*analogs & derivatives ; T-Lymphocytes/*drug effects; Animals ; Apoptosis ; Arachidonate 5-Lipoxygenase/physiology ; Chemokine CCL19 ; Chemokines, CC/physiology ; Cysteine/metabolism ; Fingolimod Hydrochloride ; Leukotrienes/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Propylene Glycols/pharmacology ; Receptors, Cell Surface ; Receptors, Lysophospholipid ; T-Lymphocytes/immunology

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 leukotriene C(4) transporter Abcc1 (Mrp1). Both transporters must be active for FTY720-mediated T cell migration and LN homing. Migration and homing driven by FTY720, phosphorylated FTY720, or S1P also require 5-lipoxygenase-mediated synthesis of cysteinyl leukotrienes and their efflux from the cell. FTY720-mediated LN homing events further downstream are dependent on CCL19, CCL21, VLA-4alpha, and CD44. Use of T cells deficient in 5-lipoxygenase, Abcb1, and Abcc1, and comparison of the effects of FTY720 with those of S1P, suggest a model of sequential engagement of Abcb1, SP1 receptors, 5-lipoxygenase, and Abcc1 to enhance T cell migration and homing.

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R01 HL069446 United States HL NHLBI NIH HHS; R01 AI049653 United States AI NIAID NIH HHS; AI49653 United States AI NIAID NIH HHS; R01 AI41428 United States AI NIAID NIH HHS; HL69446 United States HL NHLBI NIH HHS; R01 AI041428 United States AI NIAID NIH HHS

0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
0 (Ccl19 protein, mouse)
0 (Chemokine CCL19)
0 (Chemokines, CC)
0 (Immunosuppressive Agents)
0 (Leukotrienes)
0 (Lysophospholipids)
0 (Multidrug Resistance-Associated Proteins)
0 (Propylene Glycols)
0 (Receptors, Cell Surface)
0 (Receptors, G-Protein-Coupled)
0 (Receptors, Lysophospholipid)
0 (cysteinyl-leukotriene)
26993-30-6 (sphingosine 1-phosphate)
EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
G926EC510T (Fingolimod Hydrochloride)
K848JZ4886 (Cysteine)
NGZ37HRE42 (Sphingosine)
Y49M64GZ4Q (multidrug resistance-associated protein 1)

Date Created: 20030306 Date Completed: 20030402 Latest Revision: 20201222

20231215

PMC151892

10.1172/JCI16200

12618517