生物通报道：来自加州大学旧金山分校心血管研究院（Cardiovascular Research Institute），生物制药科学系，微生物与免疫学系，以及霍华德休斯医学院的研究人员发现目前作为临床实验的免疫抑制和自身免疫药物的靶标的1磷酸鞘氨醇（sphingosine-1-phosphate，S1P）除了已知的一种来源之外还存在另外一种来源，这也许提出了一种免疫抑制和S1P途径激活的改进方法，有利于免疫抑制药物的设计。这一研究成果由加州大学旧金山分校的两名教授研究小组联合完成，发表在3月15日的《Science》杂志上。

原文检索：
Published Online March 15, 2007
Science DOI: 10.1126/science.1139221
Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate 
[Abstract]

1-磷酸鞘氨醇(Sphingosine-1-phosphate ，S1P)是鞘磷脂代谢过程中产生的一种重要信号分子，可与多条信号通路交联而产生广泛的生物学效应。T细胞表达5种S1P受体，即S1P1-S1P5，S1P信号可以调节T细胞的多种免疫效应，包括T细胞增殖和凋亡、T细胞向Th2细胞分化、细胞因子分泌及T细胞迁移等。抑制S1P信号通路的药物FTY720可将T细胞阻滞于次级淋巴器官，造成外周血T细胞显著减少而发挥强烈的免疫抑制作用。

S1P原本储存在红细胞内，在发炎反应中S1P由活化的红细胞释放，然而在这篇文章中，研究人员利用一种特殊的小鼠——这种小鼠产生S1P的两个激酶被条件性敲除了，发现帮助淋巴细胞进入血液的S1P分子来自红血细胞，而帮助淋巴细胞进入淋巴系统的S1P则另有来源。

研究人员认为这种不同的来源可以帮助淋巴细胞从淋巴器官低S1P环境中退出，从而使淋巴细胞跟随一个淋巴组织和两个循环系统形成梯度。这将可能将可以帮助改进免疫抑制和S1P路径激活，用于设计免疫抑制药物。
（生物通：张迪）

附：
Jason G. Cyster, Ph.D. 

Dr. Cyster is also Professor of Microbiology and Immunology at the University of California, San Francisco. He was an undergraduate at the University of Western Australia and a graduate student at the University of Oxford, where he worked on T cell surface molecules in the laboratory of Alan Williams. His postdoctoral training was done at Stanford University with Christopher Goodnow, where he studied mechanisms of B cell tolerance.

RESEARCH ABSTRACT SUMMARY:

Jason Cyster's laboratory studies how lymphocytes and antigen-presenting cells come together to generate anti-pathogen immune responses. Cyster's group focuses on characterizing the molecular cues that guide leukocyte movements within lymphoid organs. In parallel studies they address the basis for autoreactive B cell elimination in these organs.


Shaun R. Coughlin, M.D., Ph.D.
Director, Cardiovascular Research Institute (CVRI); Professor of Medicine and Cellular and Molecular 
Pharmacology

Current work focuses on:
PAR activation. We are examining possible PAR-PAR interactions and novel cofactor mechanisms.

Receptor trafficking. The irreversibility of PAR1's proteolytic activation mechanism raises the question of how its signaling is terminated. We are using biochemical and somatic cell genetic approaches to identify how activated PAR1 is internalized and sorted to lysosomes.

PARs and platelets. To define the roles of PARs in vivo, we generated mice deficient in PAR1, PAR2, and PAR3; a PAR4 knockout is in progress. We are testing a model in which PAR3 and PAR4 mediate activation of mouse platelets and PAR1 and PAR4 activate human platelets.

PARs in embryonic development. Thrombin's not just for coagulation anymore? Approximately half of PAR1-deficient mouse embryos die at ~E9.5, apparently from bleeding. It appears that the "coagulation" system plays an unanticipated role in embryonic development that is unrelated to hemostasis in the usual sense. We are testing the hypothesis that the coagulation cascade functions as a "leak detector" that monitors and regulates vascular development, and that defective thrombin signaling in endothelial cells impairs blood vessel formation.

Other collaborative projects focus on the structural basis of GPCR signaling.