RT Journal Article
SR Electronic
T1 Modulation of chemokines and allergic airway inflammation by selective local S1P1 agonism in lung
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.066811
DO 10.1124/mol.110.066811
A1 David Marsolais
A1 Saiko Yagi
A1 Tomoyuki Kago
A1 Nora Leaf
A1 Hugh Rosen
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/10/08/mol.110.066811.abstract
AB Sphingosine-1-phosphate and its receptors have emerged as important modulators of the immune response. The sphingosine-1-phosphate pro-drug 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 to the contribution of S1P1 signaling to eosinophilic airway inflammation induced in ovalbumin-immunized mice by airway challenges with ovalbumin. Airways delivery of receptor-non-selective sphingosine-1-phosphate pro-drug 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 cell and eosinophils in the airways. Systemic delivery of sphingosine-1-phosphate pro-drug 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.