Role of S1P/S1PR3 axis in release of CCL20 from human bronchial epithelial cells

PLoS One. 2018 Sep 7;13(9):e0203211. doi: 10.1371/journal.pone.0203211. eCollection 2018.

Abstract

Background: Sphingosine 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.

Methods: The 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.

Results: S1P 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.

Conclusions: S1P/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Asthma / drug therapy
  • Asthma / genetics
  • Asthma / metabolism
  • Bronchi / immunology*
  • Bronchi / metabolism*
  • Bronchi / pathology
  • Cell Line
  • Chemokine CCL20 / metabolism*
  • Disease Models, Animal
  • Eosinophilia / drug therapy
  • Eosinophilia / pathology
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Lysophospholipids / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Phosphoserine / analogs & derivatives
  • Phosphoserine / pharmacology
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • Receptors, Prostaglandin E, EP4 Subtype / genetics
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors

Substances

  • ADRB2 protein, human
  • Anti-Inflammatory Agents
  • CCL20 protein, human
  • Chemokine CCL20
  • Lysophospholipids
  • PTGER4 protein, human
  • Receptors, Adrenergic, beta-2
  • Receptors, Lysosphingolipid
  • Receptors, Prostaglandin E, EP4 Subtype
  • S1pr1 protein, mouse
  • S1pr3 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • VPC23019
  • sphingosine-1-phosphate receptor-3, human
  • Phosphoserine
  • sphingosine 1-phosphate
  • Sphingosine

Grants and funding

This work was supported by JSPS KAKENHI 16K19453 and GSK Japan Research Grant 2017 to Masatsugu Yamamoto, JSPS KAKENHI 23591119 to Kazuyuki Kobayashi, and JSPS KAKENHI 24591131 to Yoshihiro Nishimura. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.