Unique compound with anti-allergic action: inhibition of Lyn kinase activity by KIRA6.

Mast cells and basophils play important roles in allergic disorders associated with specific antigens and IgE. Crosslinking of the high-affinity IgE receptor (FcεRI) by specific antigens activates several tyrosine kinases, such as Lyn and spleen-associated tyrosine kinase (Syk), resulting in the release of calcium ions (Ca) from the endoplasmic reticulum (ER) into the cytoplasm. As Ca release from the ER is essential for the release of pro-inflammatory mediators, ER stress-related molecules, such as inositol-requiring enzyme 1α (IRE1α), may play roles in mast cell and basophil activation. However, the associations between ER stress-related molecules and mast cell and basophil activation remain unclear. In this study, we aimed to investigate the roles of ER stress-related molecules in mast cell and basophil activation. Activation of the IRE1α-spliced form of the X-box binding protein 1 (sXBP1) axis, an ER stress-related pathway, was observed during the antigen-induced activation of mast cells. Moreover, the IRE1α inhibitor, KIRA6, suppressed antigen-induced release of pro-inflammatory mediators from rat basophilic leukemia (RBL)-2H3 cells, bone marrow-derived mast cells (BMMCs), human basophils, and human mast cells at low doses (<1 μM). However, to our surprise, IRE1α knockout did not inhibit antigen-induced release of pro-inflammatory mediators. Instead, KIRA6 blocked the antigen-induced activation of Syk by inhibiting kinase activity of Lyn. Additionally, KIRA6 exerted anti-allergic effects . Overall, our findings suggest that KIRA6 prevents allergic reactions by inhibiting the kinase activity of Lyn via an IRE1α-independent pathway.