RT Journal Article
SR Electronic
T1 Modulation of Chemokines and Allergic Airway Inflammation by Selective Local Sphingosine-1-phosphate Receptor 1 Agonism in Lungs
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 61
OP 68
DO 10.1124/mol.110.066811
VO 79
IS 1
A1 Marsolais, David
A1 Yagi, Saiko
A1 Kago, Tomoyuki
A1 Leaf, Nora
A1 Rosen, Hugh
YR 2011
UL http://molpharm.aspetjournals.org/content/79/1/61.abstract
AB 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.