Fingolimod hydrochloride (FTY720) , a novel immune modulator, is a sphingosine 1-phosphate (S1P) antagonist (IC50: 0.033 nM in K562 and NK cells).

S1P:0.033 nM (K562 and NK cells)

K562细胞和NK细胞的培养物在2μM S1P和递增浓度的Fingolimod (FTY720)存在下孵育。FTY720不同浓度的添加阻断了S1P的抑制效应，其IC50值计算为0.033 nM。S1P与FTY720的组合未影响iDCs表面这些分子的表达。此外，单独孵育10 nM FTY720对共刺激分子的表达无影响[1]。FTY720能够减少体外的兴奋毒性神经元死亡。FTY720在LPS激活的小胶质细胞中负向调节p38 MAPK，而对JNK1/2激活无影响[2]。

免疫调节剂Fingolimod的给药增加了血清S1P水平，改善了受损的心脏收缩功能，并激活了心脏中的PI3K途径。当使用S1P受体2（S1P2）拮抗剂或PI3K抑制剂后，Fingolimod的心脏保护效果被消除。缺乏鞘氨醇激酶-2的小鼠具有较高的内源性S1P水平，并且与野生型小鼠相比，LPS/PepG诱导的受损心脏收缩功能得到了减轻[3]。在NOD/SCIDγc(-/-)小鼠中使用人类ALL异种移植物，三种Ph(+)人类ALL异种移植物对Fingolimod的反应显示出在早期治疗开始时疾病总体减少了80±12%。相比之下，使用四种不同的人类Ph(-) ALL异种移植物对Fingolimod的治疗并未能减少白血病，与对照组相比没有差异[4]。

DCs or NK cells were incubated at a cell concentration of 1 × 10^6 cells/ml with either media or with 2 μM S1P, 10 nM SEW2871, 10 nM FTY720 or their combinations. DCs were also incubated with 1 μg/ml LPS. After 24 h incubation, the cells were harvested and the cell suspensions were centrifuged at 1,000 × g for 10 min before the supernatants were collected. Detection of the levels of various cytokines and chemokines was carried utilizing the Multi-Analyte ELISArray Kit as described by the manufacturers' user manual [1].

This study was carried out on 2-month-old male C57BL/6J mice or sphingosine kinase-2 deficient (SPHK-2?/?) mice weighing 25–30?g, receiving a standard diet and water ad libitum. C57BL/6J wild-type or SPHK-2?/? mice received i.p.-injections of LPS (9?mg/kg)/PepG (1?mg/kg) or its vehicle (0.9% saline). Sham mice were not subjected to LPS/PepG but were otherwise treated in the same way. At 1?h after LPS/PepG challenge, mice were treated with FTY720 (0.1?mg/kg i.v.) or its vehicle (10% DMSO). To elucidate the role of different S1P receptors in the observed effects of FTY720, mice received (45?min after LPS/PepG and 15?min prior to FTY720) the selective phosphatidylinositol 3 (PI3)-kinase inhibitor LY294002 (0.3?mg/kg i.v.) or the selective S1P2 receptor antagonist JTE 013 (1?mg/kg i.v.) or (1?h after LPS/PepG) the selective S1P1 receptor agonist SEW2871 (1?mg/kg i.v.) or vehicle (10% DMSO) [3].