FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P(3) and phosphoinositide 3-kinase.
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.
Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland.
Faik
F
Imeri
Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland.
Olivier
O
Blanchard
Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland.
Aurelio
A
Jenni
Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland.|Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
Stephanie
S
Schwalm
Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland.|Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
Christin
C
Wünsche
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine-University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
Aleksandra
A
Zivkovic
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine-University Düsseldorf, Universitätsstr. 1, 40225, Düsseldorf, Germany.
Holger
H
Stark
Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
Josef
J
Pfeilschifter
Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland. huwiler@pki.unibe.ch.
Andrea
A
Huwiler
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002080:Butterflies; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000302:isolation & purification / Q000494:pharmacology; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D020298:U937 Cells
D000893:Anti-Inflammatory Agents; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D019869:Phosphatidylinositol 3-Kinases; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C501285:S1pr3 protein, mouse
CD44; Endothelial cells; FTY720; Immune cell adhesion; ST-1071; ST-968; Sphingosine-1-phosphate