FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase
FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase
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DOI：
10.1007/s00210-015-1159-5
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发表时间：
2015-12-01
影响因子：
3.6
通讯作者：
Huwiler, Andrea
中科院分区：
文献类型：
--
作者：
Imeri, Faik;Blanchard, Olivier;Huwiler, Andrea
Sphingosine-1-phosphate (S1P) is a key lipid regulator of a variety of cellular responses including cell proliferation and survival, cell migration, and inflammatory reactions. Here, we investigated the effect of S1P receptor activation on immune cell adhesion to endothelial cells under inflammatory conditions. We show that S1P reduces both tumor necrosis factor (TNF)-alpha- and lipopolysaccharide (LPS)-stimulated adhesion of Jurkat and U937 cells to an endothelial monolayer. The reducing effect of S1P was reversed by the S1P(1+3) antagonist VPC23019 but not by the S1P(1) antagonist W146. Additionally, knockdown of S1P(3), but not S1P(1), by short hairpin RNA (shRNA) abolished the reducing effect of S1P, suggesting the involvement of S1P(3). A suppression of immune cell adhesion was also seen with the immunomodulatory drug FTY720 and two novel butterfly derivatives ST-968 and ST-1071. On the molecular level, S1P and all FTY720 derivatives reduced the mRNA expression of LPS- and TNF-alpha-induced adhesion molecules including ICAM-1, VCAM-1, E-selectin, and CD44 which was reversed by the PI3K inhibitor LY294002, but not by the MEK inhibitor U0126.In summary, our data demonstrate a novel molecular mechanism by which S1P, FTY720, and two novel butterfly derivatives acted anti-inflammatory that is by suppressing gene transcription of various endothelial adhesion molecules and thereby preventing adhesion of immune cells to endothelial cells and subsequent extravasation.
