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.
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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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