Sphingosine-1-phosphate (S1P) induces potent anti-inflammatory effects in vitro and in vivo by S1P receptor 4-mediated suppression of 5-lipoxygenase activity

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  • Jasmin Fettel, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Benjamin Kühn, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Nathalie A. Guillen, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Duran Sürün, University Hospital Frankfurt
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  • Marcus Peters, Mineralogie und Geophysik
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  • Rebekka Bauer, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Carlo Angioni, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Gerd Geisslinger, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Frank Schnütgen, University Hospital Frankfurt
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  • Dagmar Meyer Zu Heringdorf, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Oliver Werz, Friedrich Schiller University
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  • Patrick Meybohm, University Hospital Frankfurt
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  • Kai Zacharowski, University Hospital Frankfurt
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  • Dieter Steinhilber, Johann Wolfgang Goethe Universitat Frankfurt am Main
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  • Jessica Roos, University Hospital Frankfurt
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  • Thorsten J. Maier

Sphingosine-1-phosphate (S1P) is involved in the regulation of important cellular processes, including immune-cell trafficking and proliferation. Altered S1P signaling is strongly associated with inflammation, cancer progression, and atherosclerosis; however, the mechanisms underlying its pathophysiologic effects are only partially understood. This study evaluated the effects of S1P in vitro and in vivo on the biosynthesis of leukotrienes (LTs), which form a class of lipid mediators involved in the pathogenesis of inflammatory diseases. Here, we report for the first time that S1P potently suppresses LT biosynthesis in Ca2+-ionophore-stimulated intact human neutrophils. S1P treatment resulted in intracellular Ca2+ mobilization, perinuclear translocation, and finally irreversible suicide inactivation of the LT biosynthesis key enzyme 5-lipoxygenase (5-LO). Agonist studies and S1P receptor mRNA expression analysis provided evidence for a S1P receptor 4-mediated effect, which was confirmed by a functional knockout of S1P4 in HL60 cells. Systemic administration of S1P in wild-type mice decreased both macrophage and neutrophil migration in the lungs in response to LPS and significantly attenuated 5-LO product formation, whereas these effects were abrogated in 5-LO or S1P4 knockout mice. In summary, targeting the 5-LO pathway is an important mechanism to explain S1P-mediated pathophysiologic effects. Furthermore, agonism at S1P4 represents a novel effective strategy in pharmacotherapy of inflammation.-Fettel, J., Kühn, B., Guillen, N. A., Sürün, D., Peters, M., Bauer, R., Angioni, C., Geisslinger, G., Schnütgen, F., Meyer zu Heringdorf, D., Werz, O., Meybohm, P., Zacharowski, K., Steinhilber, D., Roos, J., Maier, T. J. Sphingosine-1-phosphate (S1P) induces potent anti-inflammatory effects in vitro and in vivo by S1P receptor 4-mediated suppression of 5-lipoxygenase activity.

OriginalsprogEngelsk
TidsskriftFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Vol/bind33
Nummer2
Sider (fra-til)1711-1726
Antal sider16
ISSN0892-6638
DOI
StatusUdgivet - 2019
Eksternt udgivetJa

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