Sphingosine‐1‐phosphate (S1P) induces potent anti‐inflammatory effectsin vitroandin vivoby S1P receptor 4‐mediated suppression of 5‐lipoxygenase activity

Abstract

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 (patho)physiologic 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 Ca-ionophore-stimulated intact human neutrophils. S1P treatment resulted in intracellular Ca 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 (patho)physiologic 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.

Alignment independent 3D-QSAR studies and molecular dynamics simulations for the identification of potent and selective S1P1 receptor agonists

“…Comparing the predicted affinities towards S1P 1 and S1P 3 receptors showed excellent selectivity for compound 452 (S1P 3 EC 50 /S1P 1 EC 50 : 13489). This level of predicted selectivity is comparable with the selectivities reported for S1P 1 agonists in clinical trials such as ozanimod [19] and siponimod [40] and much greater than that of compound 61, indicating that compound 452 is noteworthy to be evaluated in experiments for development of a potent and selective S1P 1 agonist. Moreover, among the selected compounds, compound 799 showed high predicted EC 50 value (0.68 nM) with acceptable S1P 1 over S1P 3 selectivity (5888 times), demonstrating its feasibility to be explored as a potent and selective S1P 1 agonist.…”

Potential therapeutic targets for atherosclerosis in sphingolipid metabolism

“…S1P is a bioactive lipid, primarily carried by apoM on HDL, and signals its G protein-coupled receptors, named S1PR1-5 [5], S1P is degraded by two pathways: dephosphorylation by S1P phosphatases (SPP1/2) and irreversible cleavage by S1P lyase (SPL). S1P has dual nature in the pathogenesis of atherosclerosis: S1P preserves endothelium via S1PR1/3 [121]; inhibits smooth muscle cells migration via S1PR2; and possesses anti-inflammatory properties via S1PR4 [122]; while S1P also promotes inflammatory monocyte/macrophage recruitment through S1PR2/3 [123,124]. Although it is yet not concensus, several clinical data reported that plasma S1P concentrations were negatively associated with prevalence and severity of CAD and myocardial infarction [125–130].…”

Validated LC‐MS/MS method of Sphingosine 1‐phosphate quantification in human serum for evaluation of response to radiotherapy in lung cancer

“…Thus, there is an urgent need to establish an efficient and reliable assay to quantify the S1P. At present, there is a lack of data on the relationship between the influencing factors of tumor treatment and monitoring results of S1P concentration . Previous studies have focused on the establishment of a certain method and did not apply it to the treatment and differences in specific cancer patients.…”