The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice.
The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice.
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DOI：
10.1016/j.intimp.2011.07.004
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发表时间：
2011-11
影响因子：
5.6
通讯作者：
G. Tarrasón;M. Aulí;Sanam Mustafa;V. Dolgachev;M. T. Domenech;N. Prats;María Domínguez;Rosa López;Nuria Aguilar;M. Calbet;M. Pont;G. Milligan;S. Kunkel;N. Godessart
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作者：
G. Tarrasón;M. Aulí;Sanam Mustafa;V. Dolgachev;M. T. Domenech;N. Prats;María Domínguez;Rosa López;Nuria Aguilar;M. Calbet;M. Pont;G. Milligan;S. Kunkel;N. Godessart
1-磷酸鞘氨醇（S1 P）受体激动剂，如芬戈莫德（FTY 720），是一类新型免疫调节剂。这些化合物的给药可防止淋巴细胞从初级和次级淋巴器官流出，从而导致外周血淋巴细胞减少症。虽然已经确定淋巴细胞减少症是由S1 P受体1（S1 P1）介导的，但其确切机制仍有争议。最受欢迎的假说指出，S1 P1激动剂导致淋巴细胞上细胞表面受体的内化和损失，阻止它们对S1 P产生反应。因此，S1 P1激动剂在体内将表现为受体的功能性拮抗剂。为了使这一假设有效，真正的S1 P1拮抗剂也应诱导淋巴细胞减少症。然而，据报道，S1 P1拮抗剂未能显示这种作用，反对这一概念。我们的研究表明，S1 P1拮抗剂，W146，诱导一个显着的，但短暂的小鼠血液淋巴细胞减少症和淋巴结中的CD 4+和CD 8+淋巴细胞的平行增加。用W146处理还引起成熟T细胞在胸腺髓质中的积累，此外，它诱导肺水肿。我们发现，S1 P1拮抗剂和S1 P1激动剂在体内引起淋巴细胞减少症，尽管它们在体外对受体表达的影响不同。尽管拮抗剂纯粹阻断受体，而激动剂导致其从细胞表面消失，但在两种情况下都阻止了对内源性配体的反应。我们的研究结果支持的假设，淋巴细胞减少症引起的S1 P1激动剂是由于功能拮抗S1 P1在淋巴细胞。
Agonists of the sphingosine-1-phosphate (S1P) receptors, like fingolimod (FTY720), are a novel class of immunomodulators. Administration of these compounds prevents the egress of lymphocytes from primary and secondary lymphoid organs causing peripheral blood lymphopenia. Although it is well established that lymphopenia is mediated by S1P receptor type 1 (S1P1), the exact mechanism is still controversial. The most favored hypothesis states that S1P1 agonists cause internalization and loss of the cell surface receptor on lymphocytes, preventing them to respond to S1P. Hence, S1P1 agonists would behave in vivo as functional antagonists of the receptor. For this hypothesis to be valid, a true S1P1 antagonist should also induce lymphopenia. However, it has been reported that S1P1 antagonists fail to show this effect, arguing against the concept. Our study demonstrates that a S1P1 antagonist, W146, induces a significant but transient blood lymphopenia in mice and a parallel increase in CD4+ and CD8+ lymphocytes in lymph nodes. Treatment with W146 also causes the accumulation of mature T cells in the medulla of the thymus and moreover, it induces lung edema. We show that both the S1P1 antagonist and a S1P1 agonist cause lymphopenia in vivo in spite of their different effects on receptor expression in vitro. Although the antagonist purely blocks the receptor and the agonist causes its disappearance from the cell surface, the response to the endogenous ligand is prevented in both cases. Our results support the hypothesis that lymphopenia evoked by S1P1 agonists is due to functional antagonism of S1P1 in lymphocytes.