Type I sphingosine 1-phosphate G protein-coupled receptor (SIP1) mediation of enhanced IL-4 generation by CD4 T cells from SIP1 transgenic mice
Type I sphingosine 1-phosphate G protein-coupled receptor (SIP1) mediation of enhanced IL-4 generation by CD4 T cells from SIP1 transgenic mice
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DOI：
10.4049/jimmunol.178.8.4885
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Goetzl, Edward J.
中科院分区：
文献类型：
--
作者：
Wang, Wengang;Huang, Mei-Chuan;Goetzl, Edward J.
鞘氨醇1-磷酸（SIP）是一种天然脂质介质，其通过增强Th 2活性的机制调节免疫细胞运输、Ab产生和T细胞细胞因子产生。对S1 P的反应主要由其受体在不同细胞中的不同表达模式控制。在T细胞中，1型（S1 P（1））和4型（S1 P（4））G蛋白偶联受体占主导地位。S1 P（1）主要转导对T细胞迁移和运输的作用，而S1 P（4）通过其对T细胞增殖和细胞因子产生的作用转导免疫抑制。我们使用T细胞特异性SIP 1转基因（TG）小鼠，研究了S1 P-S1 P（1）轴对T细胞细胞因子产生的调节作用。与野生型小鼠相比，S1 P（1）TG小鼠活化的CD 4 T细胞中IL-4的产生显著上调> 10倍，但IL-2或IFN-γ的产生没有显著上调。实时荧光定量PCR分析显示，IL-4的上调开始在mRNA水平上，早在4小时后T细胞活化。IL-4 mRNA的上调是由c-Maf、Jun B和Gata 3介导的，表现为其蛋白表达和DNA结合活性的增加。相反，T-bet、FosB、C-Fos、Jun D、Fra-1、Fra-2和c-jun的表达和DNA结合活性在野生型和TG CD 4 T细胞中均相同。免疫学分析表明，增加IL-4水平诱导更大的生产IgE。因此，S1 P-SIP 1轴特异性上调c-Maf、Jun B和Gata 3，其因此增强IL-4产生，这可能导致Th 2表型。
Sphingosine 1-phosphate (SIP) 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 SIP1 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-SIP1 axis specifically up-regulates c-Maf, Jun B, and Gata3, which consequently enhance IL-4 production that may lead to a Th2 phenotype.