title: Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.
abstract: Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 and is thought to occur in response to circulatory S1P. However, the existence of an S1P gradient between lymphoid organs and blood or lymph has not been established. To further define egress requirements, we addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. We found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after THI treatment and that this treatment inhibits the S1P-degrading enzyme S1P lyase. We conclude that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target.
authors.affiliation: Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0414, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Schwab
authors.forename: João P
authors.initials: JP
authors.lastname: Pereira
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Matloubian
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005505:Food Coloring Agents / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008196:Lymph / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D008231:Lymphopenia / Q000139:chemically induced; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011736:Pyridoxine / Q000031:analogs & derivatives / Q000494:pharmacology; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D025101:Vitamin B 6 / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005505:Food Coloring Agents; D007093:Imidazoles; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; C004675:4-deoxypyridoxine; D025101:Vitamin B 6; C049929:2-acetyl-4(5)-tetrahydroxybutylimidazole; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D011736:Pyridoxine; D013110:Sphingosine