Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation.
Sphingosine 1-phosphate (S1P) is a pleiotropic lysosphingophospholipid stored and secreted by platelets. Using reverse transcription-polymerase chain reaction and flow cytometric analyses, we determined the expression of S1P receptors (S1P1, S1P3, S1P4, and S1P5) in peripheral blood T cells. T cells were induced to proliferate in the presence of phorbol 12-myristate 13-acetate (PMA) plus ionomycin, anti-CD3 plus anti-CD28, and allogeneic immature or mature dendritic cells. This activity was inhibited by the addition of S1P. Enhanced T-cell proliferation was observed when these cells were stimulated with the same stimuli, but were incubated in serum-free media (SFM). Addition of S1P to SFM inhibited the stimulation of T cells induced by T-cell stimuli, suggesting that S1P is an important inhibitory molecule present in the serum. T-cell proliferation was also inhibited by the addition of dihydrosphingosine 1-phosphate (DHS1P), sphingosine, and ceramide; however, the latter 2 sphingolipids required higher concentrations than S1P. Pretreatment of T cells with pertussis toxin (PTX) blocked the inhibitory effect of S1P on activation with PMA plus ionomycin, but not on activation with anti-CD3 plus anti-CD28. This is corroborated with the down-regulation of S1P1 in T cells stimulated with anti-CD3 plus anti-CD28. Similarly, PTX did not affect the inhibitory effect of S1P on T-cell proliferation when dendritic cells were used as stimuli. Further, S1P or DHS1P but not ceramide or sphingosine enhanced rather than decreased secretion of interleukin 2 and interferon gamma by T cells stimulated with anti-CD3 plus anti-CD28. These results show differential effects of S1P on polyclonal T-cell proliferation and cytokine secretion.
Jin
Yixin
Y
Department of Anatomy and Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway.
Knudsen
Eirunn
E
Wang
Ling
L
Bryceson
Yenan
Y
Damaj
Bassam
B
Gessani
Sandra
S
Maghazachi
Azzam A
AA
D000906:Antibodies / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division / Q000187:drug effects*; D003470:Culture Media; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008246:Lysophospholipids; D037342:Pertussis Toxin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D049312:Receptors, Lysophospholipid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D003470:Culture Media; D007376:Interleukin-2; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; C060506:sphingosine 1-phosphate; D015759:Ionomycin; D007371:Interferon-gamma; D037342:Pertussis Toxin; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate