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Research ArticleArticle

Modulation of Chemokines and Allergic Airway Inflammation by Selective Local Sphingosine-1-phosphate Receptor 1 Agonism in Lungs

David Marsolais, Saiko Yagi, Tomoyuki Kago, Nora Leaf and Hugh Rosen
Molecular Pharmacology January 2011, 79 (1) 61-68; DOI: https://doi.org/10.1124/mol.110.066811
David Marsolais
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Saiko Yagi
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Tomoyuki Kago
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Nora Leaf
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Hugh Rosen
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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 (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 S1P1-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.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grants AI05509, AI074564]; the National Institutes of Health National Institute on Mental Health [Grant MH074404]; by a grant from Kyorin Pharmaceuticals [SFP-1799]; by Le Fonds de la Recherche en Santé du Québec (FRSQ); the Respiratory Health Network of FRSQ; and the La Chaire de Pneumologie de la Fondation J-D Bégin de l'Université Laval et de la Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.066811.

  • ABBREVIATIONS:

    S1P
    sphingosine-1-phosphate
    S1P1–S1P5
    sphingosine-1-phosphate receptors 1 to 5
    SK
    sphingosine kinase
    FTY720
    2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol
    AAI
    allergic airway inflammation
    AAL-R
    (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol
    OVA
    ovalbumin
    CYM-5442
    2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol
    BALF
    bronchoalveolar lavage fluid
    PBS
    phosphate-buffered saline
    DC
    dendritic cell
    DMSO
    dimethyl sulfoxide
    CFSE
    carboxyl-fluorescein diacetate, succinimidyl ester
    CTR
    control
    OVA/OVA mice
    mice sensitized and then challenged with OVA
    VEH
    vehicle
    TARC
    thymus- and activation-regulated chemokine
    RANTES
    regulated upon activation, normal T-cell expressed, and secreted
    CXCR
    chemokine CXC motif receptor
    CCR
    chemokine receptor
    W146
    3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid
    SEW2871
    5-[4-phenyl-5-(trifluoromethyl)thiophen-2-yl]-3-[3-(trifluoromethyl)phenyl]1,2,4-oxadiazole
    AUY954
    3-(((2-(2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)benzo[b]thiophen-5-yl)methyl)amino)propanoic acid.

  • Received June 9, 2010.
  • Accepted October 7, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (1)
Molecular Pharmacology
Vol. 79, Issue 1
1 Jan 2011
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Research ArticleArticle

Modulation of Chemokines and Allergic Airway Inflammation by Selective Local Sphingosine-1-phosphate Receptor 1 Agonism in Lungs

David Marsolais, Saiko Yagi, Tomoyuki Kago, Nora Leaf and Hugh Rosen
Molecular Pharmacology January 1, 2011, 79 (1) 61-68; DOI: https://doi.org/10.1124/mol.110.066811

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Research ArticleArticle

Modulation of Chemokines and Allergic Airway Inflammation by Selective Local Sphingosine-1-phosphate Receptor 1 Agonism in Lungs

David Marsolais, Saiko Yagi, Tomoyuki Kago, Nora Leaf and Hugh Rosen
Molecular Pharmacology January 1, 2011, 79 (1) 61-68; DOI: https://doi.org/10.1124/mol.110.066811
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