Abstract
BackgroundSphingosine kinase phosphorylates sphingosine to generate sphingosine 1 phosphate (S1P) following stimulation of the five plasma membrane G-protein-coupled receptors. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells.MethodsThe effects of S1P on asthma-related genes expression were examined with the human bronchial epithelial cells BEAS-2B and Calu-3 using a transcriptome analysis and siRNA of S1PRs. To clarify the role of CCL20 in the airway inflammation, BALB/c mice were immunized with ovalbumin (OVA) and subsequently challenged with an OVA-containing aerosol to induce asthma with or without intraperitoneal administration of anti-CCL20. Finally, the anti-inflammatory effect of VPC 23019, S1PR1/3 antagonist, in the OVA-induced asthma was examined.ResultsS1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells. The knock-down of SIPR3 suppressed the expression of S1P-inducing CCL20. Anti-CCL20 antibody significantly attenuated the eosinophil numbers in the bronchoalveolar lavage fluid (P<0.01). Upon OVA challenge, VPC23019 exhibited substantially attenuated eosinophilic inflammation.ConclusionsS1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells. Our results suggest that S1P/S1PR3 may be a possible candidate for the treatment of bronchial asthma.
Highlights
Sphingosine 1 phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological responses such as proliferation, migration, cytoskeletal organization, adherent junction assembly and morphogenesis [1]
S1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells
S1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells
Summary
Sphingosine 1 phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological responses such as proliferation, migration, cytoskeletal organization, adherent junction assembly and morphogenesis [1]. S1P is exported outside of cells by ATP-binding cassette-type or other transporters and extracellular S1P activates five G protein-coupled receptors, known as S1P receptors (S1PRs) 1–5 via autocrine and paracrine signaling [2]. S1PR1 has a role in lymphocyte trafficking, from the lymph nodes or thymus to the lymph or blood and in dendritic cell (DC) maturation [2]. The localizations of S1PRs are well-characterized, and the physiological role of the interaction between S1P and S1PRs in the immune cell function has been clarified using FTY720, which is a prodrug that is phosphorylated in vivo by sphingosine kinases (SPHK) 2 to biologically active FTY720-phosphate [3]. FTY720-phosphate binds to S1PRs except for S1PR2. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells
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