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

Abstract

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)-α- and lipopolysaccharide (LPS)-stimulated adhesion of Jurkat and U937 cells to an endothelial monolayer. The reducing effect of S1P was reversed by the S1P1+3 antagonist VPC23019 but not by the S1P1 antagonist W146. Additionally, knockdown of S1P3, but not S1P1, by short hairpin RNA (shRNA) abolished the reducing effect of S1P, suggesting the involvement of S1P3. 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-α-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.

FTY720 Attenuates Retinal Inflammation and Protects Blood–Retinal Barrier in Diabetic Rats

“…16 Apart from induction of lymphopenia, a novel molecular mechanism by which FTY720 exerts anti-inflammatory effect has been reported: suppressing gene transcription of endothelial adhesion molecules and thereby preventing adhesion of immune cells to endothelial cells and subsequent extravasation through activation of S1P3. 58 Our results showed that FTY720 inhibits ICAM-1 and VCAM-1 expression while promoting gene transcription of S1P3 in diabetic rats. We therefore postulate that FTY720 may suppress leukocyte adhesion and subsequent BRB breakdown via up-regulation of S1P3, contributing to its protection in DR.…”

Sphingosine-1-phosphate in anti-neutrophil cytoplasmic antibody-associated vasculitis: coagulation-related clinical indicators and complications

“…Moreover, C5a triggers the activation of ANCA, thereby activating the coagulation system and producing thrombin [ 48 , 51 ]. Because S1P is a critical factor in C5a-mediated neutrophil activation, it can potentially play a role in the inflammatory and coagulation systems [ 48 , 52 ]. S1P interacts with C5a to cause ANCA-induced neutrophil respiratory bursts and degradation in AAV.…”

Impact of S1P Mimetics on Mesenteric Ischemia/Reperfusion Injury

“…Interestingly, the decrease in neutrophil migration could be explained by the blockade of leukotrienes biosynthesis caused by the 5-lipoxygenase inhibition brought about by the S1P 4 receptor activation [ 27 ]. With regard to the S1P 3 receptor activation, FTY720 has also been demonstrated to downregulate the in vitro expression of adhesion molecules on endothelial cells through S1P 3 via PI3K activation [ 28 ], a feature possibly reducing immune cell transmigration into inflamed areas.…”