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

FASEB J. 2019 Feb;33(2):1711-1726. doi: 10.1096/fj.201800221R. Epub 2018 Sep 6.


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.

Keywords: calcium; inactivation of 5-LO; inflammation; leukotriene formation; lipid mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Arachidonate 5-Lipoxygenase / biosynthesis
  • Arachidonate 5-Lipoxygenase / drug effects*
  • Arachidonate 5-Lipoxygenase / metabolism
  • Arachidonic Acid / metabolism
  • Calcium / metabolism
  • Cell Line
  • Female
  • Humans
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / enzymology
  • Neutrophils / metabolism
  • Pneumonia / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Receptors, Lysosphingolipid / physiology*
  • Signal Transduction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Substrate Specificity


  • Anti-Inflammatory Agents
  • Lysophospholipids
  • Reactive Oxygen Species
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Arachidonic Acid
  • Arachidonate 5-Lipoxygenase
  • Sphingosine
  • Calcium