Suppressive Effect of CYM50358 S1P4 Antagonist on Mast Cell Degranulation and Allergic Asthma in Mice

Abstract

Levels of sphingosine 1-phosphate (S1P), an intercellular signaling molecule, reportedly increase in the bronchoalveolar lavage fluids of patients with asthma. Although the type 4 S1P receptor, S1P(4) has been detected in mast cells, its functions have been poorly investigated in an allergic asthma model in vivo. S1P(4) functions were evaluated following treatment of CYM50358, a selective antagonist of S1P(4), in an ovalbumin-induced allergic asthma model, and antigen-induced degranulation of mast cells. CYM50358 inhibited antigen-induced degranulation in RBL-2H3 mast cells. Eosinophil accumulation and an increase of Th2 cytokine levels were measured in the bronchoalveolar lavage fluid and via the inflammation of the lungs in ovalbumin-induced allergic asthma mice. CYM50358 administration before ovalbumin sensitization and before the antigen challenge strongly inhibited the increase of eosinophils and lymphocytes in the bronchoalveolar lavage fluid. CYM50358 administration inhibited the increase of IL-4 cytokines and serum IgE levels. Histological studies revealed that CYM50358 reduced inflammatory scores and PAS (periodic acid-Schiff)-stained cells in the lungs. The pro-allergic functions of S1P(4) were elucidated using in vitro mast cells and in vivo ovalbumin-induced allergic asthma model experiments. These results suggest that S1P(4) antagonist CYM50358 may have therapeutic potential in the treatment of allergic asthma.