Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.
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.
Schwab
Susan R
SR
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0414, USA.
Pereira
João P
JP
Matloubian
Mehrdad
M
Xu
Ying
Y
Huang
Yong
Y
Cyster
Jason G
JG
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
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