Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice.
Sphingosine 1-phosphate (S1P) is a natural lipid mediator that regulates immune cell traffic, Ab production, and T cell cytokine generation by mechanisms that enhance Th2 activities. Responses to S1P are controlled principally by the diverse expression patterns of its receptors in different cells. In T cells, the type 1 (S1P(1)) and type 4 (S1P(4)) G protein-coupled receptors are predominant. S1P(1) mainly transduces effects on T cell migration and trafficking, whereas S1P(4) transduces immunosuppression via its effects on T cell proliferation and cytokine production. Using T cell-specific S1P(1) transgenic (TG) mice, we investigated the regulatory effects of the S1P-S1P(1) axis on T cell cytokine production. The production of IL-4, but not IL-2 or IFN-gamma, was significantly up-regulated >10-fold in activated CD4 T cells from S1P(1) TG mice compared with those from wild-type mice. Quantitative real-time PCR analysis revealed that IL-4 up-regulation was initiated at the mRNA level as early as 4 h after T cell activation. The up-regulation of IL-4 mRNA was mediated by c-Maf, Jun B, and Gata3 as demonstrated by increases in their protein expression and DNA-binding activities. In contrast, the expression and DNA-binding activities of T-bet, FosB, C-Fos, Jun D, Fra-1, Fra-2, and c-Jun all were identical in wild-type and TG CD4 T cells. Immunological assays showed that increased IL-4 levels induced greater production of IgE. Thus, the S1P-S1P(1) axis specifically up-regulates c-Maf, Jun B, and Gata3, which consequently enhance IL-4 production that may lead to a Th2 phenotype.
Wang
Wengang
W
Department of Medicine and Department of Microbiology-Immunology, University of California, San Francisco, CA 94143.
Huang
Mei-Chuan
MC
Goetzl
Edward J
EJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D007073:Immunoglobulin E / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D049349:Receptors, Lysosphingolipid / Q000502:physiology*
D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D015847:Interleukin-4; D007073:Immunoglobulin E