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PMID: 12618517 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 111 ·No. 5 ·2003-03-00 ·Pages 627-37

Honig SM, Fu S, Mao X, Yopp A, Gunn MD, Randolph GJ, Bromberg JS

Abstract

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.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology Animals Apoptosis Arachidonate 5-Lipoxygenase/physiology Chemokine CCL19 Chemokines, CC/physiology Chemotaxis, Leukocyte/drug effects Cysteine/metabolism,physiology Fingolimod Hydrochloride Immunosuppressive Agents/pharmacology Leukotrienes/metabolism,physiology Lymph Nodes/immunology Lysophospholipids Mice Mice, Inbred C57BL Multidrug Resistance-Associated Proteins/physiology Phosphorylation Propylene Glycols/pharmacology Receptors, Cell Surface Receptors, G-Protein-Coupled Receptors, Lysophospholipid Sphingosine/analogs & derivatives T-Lymphocytes/drug effects,immunology
Chemicals
ATP Binding Cassette Transporter, Subfamily B, Member 1 Ccl19 protein, mouse Chemokine CCL19 Chemokines, CC Immunosuppressive Agents Leukotrienes Lysophospholipids Multidrug Resistance-Associated Proteins Propylene Glycols Receptors, Cell Surface Receptors, G-Protein-Coupled Receptors, Lysophospholipid cysteinyl-leukotriene sphingosine 1-phosphate Arachidonate 5-Lipoxygenase Fingolimod Hydrochloride Cysteine Sphingosine multidrug resistance-associated protein 1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Honig Shaun M
Carl C. Icahn Center For Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Fu Shuang
Mao Xia
Yopp Adam
Gunn Michael D
Randolph Gwendalyn J
Bromberg Jonathan S
References (47)
47 references, click to expand
  1. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene.
    Nature. 1994 Nov 10;372(6502):179-82 PMID: 7969451
  2. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates.
    J Biol Chem. 1994 Nov 11;269(45):27807-10 PMID: 7961706
  3. Diacylglycerol lipase activation and 5-lipoxygenase activation and translocation following TCR/CD3 triggering in T cells.
    Eur J Immunol. 1995 Apr;25(4):1080-6 PMID: 7737277
  4. Lymphocyte homing and homeostasis.
    Science. 1996 Apr 5;272(5258):60-6 PMID: 8600538
  5. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine.
    Cell. 1996 Nov 1;87(3):507-17 PMID: 8898203
  6. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4028-33 PMID: 9108099
  7. Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione.
    Cancer Res. 1997 Dec 1;57(23):5238-42 PMID: 9393741
  8. Pharmacologic approaches to reversing multidrug resistance.
    Semin Hematol. 1997 Oct;34(4 Suppl 5):40-7 PMID: 9408960
  9. A multidrug-resistance protein (MRP)-like transmembrane pump is highly expressed by resting murine T helper (Th) 2, but not Th1 cells, and is induced to equal expression levels in Th1 and Th2 cells after antigenic stimulation in vivo.
    J Clin Invest. 1998 Feb 1;101(3):703-10 PMID: 9449706
  10. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4.
    Blood. 1998 Apr 15;91(8):2886-95 PMID: 9531599
  11. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing.
    J Immunol. 1998 May 15;160(10):5037-44 PMID: 9590253
  12. Abortive proliferation of rare T cells induced by direct or indirect antigen presentation by rare B cells in vivo.
    J Exp Med. 1998 May 18;187(10):1611-21 PMID: 9584139
  13. A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels.
    Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6924-9 PMID: 9618515
  14. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3.
    Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8205-10 PMID: 9653165
  15. Secondary lymphoid-tissue chemokine (SLC) stimulates integrin alpha 4 beta 7-mediated adhesion of lymphocytes to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) under flow.
    J Immunol. 1998 Jul 15;161(2):952-6 PMID: 9670974
  16. Antigen localization and migration in immunity and tolerance.
    N Engl J Med. 1998 Dec 24;339(26):1905-13 PMID: 9862947
  17. The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane.
    J Cell Sci. 1999 Feb;112 ( Pt 3):415-22 PMID: 9885294
  18. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.
    J Exp Med. 1999 Feb 1;189(3):451-60 PMID: 9927507
  19. Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment.
    Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11452-7 PMID: 10500197
  20. Secretion of platelet-activating factor is mediated by MDR1 P-glycoprotein in cultured human mesangial cells.
    J Am Soc Nephrol. 1999 Nov;10(11):2306-13 PMID: 10541289
  21. Cutting edge: identification of a novel chemokine receptor that binds dendritic cell- and T cell-active chemokines including ELC, SLC, and TECK.
    J Immunol. 2000 Mar 15;164(6):2851-6 PMID: 10706668
  22. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion.
    Mol Cell Biol. 2000 Jun;20(11):4106-14 PMID: 10805752
  23. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory.
    J Immunol. 2000 Jun 1;164(11):5761-70 PMID: 10820254
  24. Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue.
    Nat Med. 2000 Jun;6(6):686-8 PMID: 10835686
  25. Cutting edge: hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation.
    J Immunol. 2000 Jul 1;165(1):15-9 PMID: 10861029
  26. Specialized contributions by alpha(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels.
    Immunity. 2000 Jun;12(6):665-76 PMID: 10894166
  27. Immunosuppressant FTY720 induces apoptosis by direct induction of permeability transition and release of cytochrome c from mitochondria.
    J Immunol. 2000 Sep 15;165(6):3250-9 PMID: 10975841
  28. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes.
    Cell. 2000 Nov 22;103(5):757-68 PMID: 11114332
  29. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression.
    Immunol Rev. 2000 Oct;177:134-40 PMID: 11138771
  30. Sphingosine kinase: a mediator of vital cellular functions.
    Prostaglandins Other Lipid Mediat. 2001 Apr;64(1-4):123-34 PMID: 11324702
  31. Sphingosine-1-phosphate phosphatases.
    Prostaglandins Other Lipid Mediat. 2001 Apr;64(1-4):143-56 PMID: 11324704
  32. Chemokines, chemokine receptors, and allograft rejection.
    Immunity. 2001 Apr;14(4):377-86 PMID: 11336683
  33. Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor.
    Biochem J. 2001 Aug 1;357(Pt 3):859-65 PMID: 11463358
  34. Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators.
    Semin Immunol. 2001 Oct;13(5):267-74 PMID: 11502161
  35. Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities.
    Blood. 2001 Nov 15;98(10):3022-9 PMID: 11698286
  36. Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice.
    J Immunol. 2001 Dec 1;167(11):6631-6 PMID: 11714834
  37. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720.
    J Exp Med. 2001 Dec 17;194(12):1875-81 PMID: 11748287
  38. FTY720: dissection of membrane receptor-operated, stereospecific effects on cell migration from receptor-independent antiproliferative and apoptotic effects.
    Transplant Proc. 2001 Nov-Dec;33(7-8):3078-80 PMID: 11750323
  39. L-selectin-dependent lymphoid occupancy is required to induce alloantigen-specific tolerance.
    J Immunol. 2002 Feb 15;168(4):1579-89 PMID: 11823485
  40. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position.
    Nature. 2002 Mar 7;416(6876):94-9 PMID: 11882900
  41. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
    Science. 2002 Apr 12;296(5566):346-9 PMID: 11923495
  42. Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist.
    Can J Physiol Pharmacol. 1989 Jan;67(1):17-28 PMID: 2540892
  43. Naive and memory T cells show distinct pathways of lymphocyte recirculation.
    J Exp Med. 1990 Mar 1;171(3):801-17 PMID: 2307933
  44. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells.
    Cell. 1991 Jul 12;66(1):85-94 PMID: 1712673
  45. Increased function of P-glycoprotein in T lymphocyte subsets of aging mice.
    J Immunol. 1993 Feb 15;150(4):1296-306 PMID: 8094406
  46. Extrusion of the P glycoprotein substrate rhodamine-123 distinguishes CD4 memory T cell subsets that differ in IL-2-driven IL-4 production.
    J Immunol. 1994 Jul 15;153(2):658-65 PMID: 7912705
  47. Recirculation, phenotype and functions of lymphocytes in mice treated with monoclonal antibody MEL-14.
    Eur J Immunol. 1994 Dec;24(12):3106-12 PMID: 7528669
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI16200
Published
2003-03-00
Pages
627-37
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151892
Subset
IM
Grants
NHLBI NIH HHS · R01 HL069446 · United States
NIAID NIH HHS · R01 AI049653 · United States
NIAID NIH HHS · AI49653 · United States
NIAID NIH HHS · R01 AI41428 · United States
NHLBI NIH HHS · HL69446 · United States
NIAID NIH HHS · R01 AI041428 · United States
External Links
PubMed source DOI: 10.1172/JCI16200 PMC Full Text View journal details
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