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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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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.

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Abbreviations

AMPK:

AMP-activated protein kinase

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

EAE:

Experimental autoimmune-induced encephalomyelitis

GPCR:

G protein-coupled receptor

HA:

Hyaluronic acid

ICAM-1:

Intercellular adhesion molecule-1

IκBα:

Inhibitor of κB α

LPS:

Lipopolysaccharide

NFκB:

Nuclear factor κB

PBS:

Phosphate-buffered saline

S1P:

Sphingosine-1-phosphate

SK:

Sphingosine kinase

TNF-α:

Tumor necrosis factor-α

VCAM-1:

Vascular cell adhesion molecule-1

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Acknowledgments

This work was supported by the Swiss Society for Multiple Sclerosis, the Swiss National Science Foundation (310030_135619), and the German Research Foundation (SFB 1039 to JP).

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The authors declare that they have no competing interests.

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The manuscript does not contain clinical studies or patient data.

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Correspondence to Andrea Huwiler.

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Faik Imeri, Olivier Blanchard, and Aurelio Jenni contributed equally.

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Imeri, F., Blanchard, O., Jenni, A. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 388, 1283–1292 (2015). https://doi.org/10.1007/s00210-015-1159-5

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