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Modulation of chemokines and allergic airway inflammation by selective local sphingosine-1-phosphate receptor 1 agonism in lungs

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Overview

authors

  • Marsolais, D.
  • Yagi, S.
  • Kago, T.
  • Leaf, N.
  • Rosen, Hugh

publication date

  • January 2011

journal

  • Molecular Pharmacology  Journal

abstract

  • Sphingosine-1-phosphate and its receptors have emerged as important modulators of the immune response. The sphingosine-1-phosphate prodrug 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720) can alleviate experimental allergic airway inflammation. Nevertheless, the role of individual sphingosine-1-phosphate receptors in the regulation of allergic airway inflammation remains undefined. Using a newly characterized potent and selective sphingosine-1-phosphate receptor 1 (S1P?) agonist with physical properties allowing airway delivery, we studied the contribution of S1P? signaling to eosinophilic airway inflammation induced in ovalbumin-immunized mice by airway challenges with ovalbumin. Airway delivery of receptor-nonselective sphingosine-1-phosphate prodrug significantly inhibits the sequential accumulation of antigen-presenting dendritic cells and CD4+ T cells in draining lymph nodes. This in turn suppressed by >80% the accumulation of CD4+ T cells and eosinophils in the airways. Systemic delivery of sphingosine-1-phosphate prodrug or of an S1P)?-specific agonist at doses sufficient to induce lymphopenia did not inhibit eosinophil accumulation in the airways. In contrast, local airway delivery of S1P?-specific agonist inhibited airways release of endogenous CCL5 and CCL17 chemokines, and significantly suppressed accumulation of activated T cells and eosinophils in the lungs. Specific S1P? agonism in lungs contributes significantly to anti-inflammatory activities of sphingosine-1-phosphate therapeutics by suppressing chemokine release in the airways, and may be of clinical relevance.
  • Sphingosine-1-phosphate and its receptors have emerged as important modulators of the immune response. The sphingosine-1-phosphate prodrug 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720) can alleviate experimental allergic airway inflammation. Nevertheless, the role of individual sphingosine-1-phosphate receptors in the regulation of allergic airway inflammation remains undefined. Using a newly characterized potent and selective sphingosine-1-phosphate receptor 1 (S1P₁) agonist with physical properties allowing airway delivery, we studied the contribution of S1P₁ signaling to eosinophilic airway inflammation induced in ovalbumin-immunized mice by airway challenges with ovalbumin. Airway delivery of receptor-nonselective sphingosine-1-phosphate prodrug significantly inhibits the sequential accumulation of antigen-presenting dendritic cells and CD4+ T cells in draining lymph nodes. This in turn suppressed by >80% the accumulation of CD4+ T cells and eosinophils in the airways. Systemic delivery of sphingosine-1-phosphate prodrug or of an S1P)₁-specific agonist at doses sufficient to induce lymphopenia did not inhibit eosinophil accumulation in the airways. In contrast, local airway delivery of S1P₁-specific agonist inhibited airways release of endogenous CCL5 and CCL17 chemokines, and significantly suppressed accumulation of activated T cells and eosinophils in the lungs. Specific S1P₁ agonism in lungs contributes significantly to anti-inflammatory activities of sphingosine-1-phosphate therapeutics by suppressing chemokine release in the airways, and may be of clinical relevance.

subject areas

  • Allergens
  • Animals
  • Chemokines
  • Lung
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Ovalbumin
  • Pneumonia
  • Prodrugs
  • Receptors, Lysophospholipid
  • Receptors, Lysosphingolipid
  • Thiophenes
  • beta-Alanine
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Identity

PubMed Central ID

  • PMC3014274

International Standard Serial Number (ISSN)

  • 0026-895X

Digital Object Identifier (DOI)

  • 10.1124/mol.110.066811

PubMed ID

  • 20935081
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Additional Document Info

start page

  • 61

end page

  • 68

volume

  • 79

issue

  • 1

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