Sphingosine 1-Phosphate誘發小鼠Th17細胞分化之研究

Abstract

Sphingosin 1-Phosphate（S1P）是一種由人體自然製造的小分子水解磷酸脂，其主要的來源為血小板以及被活化的巨嗜細胞。S1P已知能夠經由其第一型特異性受器（S1P1) 來調控T細胞的生長和移動，但對於型干擾素（IFN-）表現的抑制，卻是目前在cytokine的調控上，S1P唯一確定的功能。我之前的研究顯示，S1P能夠促進S1P1大量表現（S1P1-overexpressed）CD4 T細胞分化成為Th17細胞，並分泌interleukin-17（IL-17）。因此我認為，在原生型的小鼠脾臟CD4 T細胞上，S1P可能也具有相同的功能。研究結果顯示，S1P能夠增加IL-17蛋白質的表現量、抑制IFN-和IL-4的分泌，並促進Th17細胞的分化。S1P對於IL-17表現的調控，可能是經由其特異性受器S1P1來達成的。同時，S1P的功能會受到IFN-、IL-4和IL-27的抑制。細胞訊息傳遞路徑的研究指出，S1P可能是透過Gi、Protein Kinase C以及轉錄因子NF-B來誘發IL-17基因的表現。此外，我也證實了S1P1特異性抑制劑FTY720能夠有效的預防S1P所造成的IL-17表現量增加以及Th17細胞的分化。本研究為首度在體外培養（in vitro）的環境下證明，S1P能夠促進Th17細胞的分化和IL-17的表現。同時，我亦為免疫抑制劑FTY720的作用機轉，提出了一個新的理論基礎。

Sphingosine 1-phosphate (S1P) in blood and lymph controls T cell traffic and proliferation through type 1 S1P receptor (S1P1) signals, but suppression of IFN-γ generation has been the only consistently observed effect on T cell cytokines. That S1P enhances development of Th17 cells from antigen-challenged transgenic S1P1-overexpressing CD4 T cells suggested that the S1P-S1P1 axis may promote expansion of Th17 cells in wild type mice. In a model of development of Th17 cells from CD4 T cells stimulated by anti-CD3 plus anti-CD28 antibodies and a mixture of TGF-β1, IL-1 and IL-6, S1P enhanced their number and IL-17-generating activity the same as IL-23. As for IL-23 enhancement of development of Th17 cells, that by S1P was prevented by IL-4 plus IFN-γ and by IL-27. Prevention of S1P augmentation of Th17 cell development by the S1P receptor agonist and downregulator FTY720 implies that FTY720 immunosuppression is attributable partially to inhibition of Th17-mediated inflammation.