JTE‐013, an antagonist of sphingosine 1‐phosphate receptor 2, inhibits ovalbumin‐induced allergic asthma in Balb/c mice

Abstract

BackgroundActivation of sphingosine kinases 1 and 2 and secretion of sphingosine 1‐phosphate (S1P) have been implication in allergic responses, asthma and anaphylaxis. Type 1 and 2 receptors for S1P have been suggested as targets of secreted S1P functions in mast cells. However, functions of S1P receptors in vivo has not been investigated in an allergic asthma model.METHODSAntigen‐induced degranulation was measured in RBL‐2H3 mast cells by measuring b‐hexosamidase activity. An ovalbumin‐induced allergic asthma model was used for in vivo efficacy test of JTE‐013, a selective antagonist of type 2 S1P receptor.RESULTSJTE‐013 inhibited the antigen‐induced degranulation of beta‐hexosaminidase in RBL‐2H3 mast cells in a concentration‐dependent manner in vitro. Sensitization and challenge of ovalbumin induced allergic asthma responses, that is, the accumulations of eosinophils and increase of Th2 cytokine levels in bronchoalveolar lavage fluid and lung inflammation. Administration of JTE‐013 before ovalbumin sensitization or before ovalbumin challenge strongly inhibited the accumulation of eosinophils and lymphocytes to bronchoalveolar lavage fluid. JTE‐013 administration also inhibited expression and secretion of Th2 cytokines, that is, IL‐4 and IL‐13. Histologic studies showed that JTE‐013 reduced inflammatory signs in the lung.CONCLUSIONJTE‐013 has anti‐allergic effects and may be utilized as a potent agent for the treatment of asthma.