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Type 1 Sphingosine 1-Phosphate G Protein-Coupled Receptor (S1P₁) Mediation of Enhanced IL-4 Generation by CD4 T Cells from S1P₁ Transgenic Mice¹

Department of Medicine and Department of Microbiology-Immunology, University of California, San Francisco, CA 94143

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 (S1P₁) and type 4 (S1P₄) G protein-coupled receptors are predominant. S1P₁ mainly transduces effects on T cell migration and trafficking, whereas S1P₄ transduces immunosuppression via its effects on T cell proliferation and cytokine production. Using T cell-specific S1P₁ transgenic (TG) mice, we investigated the regulatory effects of the S1P-S1P₁ axis on T cell cytokine production. The production of IL-4, but not IL-2 or IFN-, was significantly up-regulated >10-fold in activated CD4 T cells from S1P₁ 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-S1P₁ axis specifically up-regulates c-Maf, Jun B, and Gata3, which consequently enhance IL-4 production that may lead to a Th2 phenotype.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R01-HL31809 from the National Institutes of Health (to E.J.G.) and the Rainin Endowed Research Fellowship.

² Address correspondence and reprint requests to Dr. Edward J. Goetzl, University of California, UB8B, Box 0711, 533 Parnassus at 4th Avenue, San Francisco, CA 94143. E-mail address: Edward.Goetzl{at}ucsf.edu

³ Abbreviations used in this paper: S1P, sphingosine 1-phosphate; TG, transgenic; WT, wild type; HPRT, hypoxanthine phosphoribosyltransferase; C_T, threshold cycle; FoxP3, forkhead box P3; GITR, glucocorticoid-induced TNF-like receptor; CHIP, chromatin immunoprecipitation; Treg, regulatory T cell; GPCR, G protein-coupled receptor.

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