Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4μ8C

Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4 mu 8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4 mu 8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4 mu 8C suppressed the degranulation of IgE-mediated mast cells (IC50 = 3.2 mu M) and the production of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) in a dose-dependent manner. 4 mu 8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50 = 25.1 mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4 mu 8C, and phosphorylation of downstream signaling molecules, such as linker for activated T cells (LAT), Akt, and the three MAP kinases, ERK, p38, and JNK, were suppressed. Mechanistic studies showed that 4 mu 8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4 mu 8C involved reduced activity of Lyn and Fyn, which is pivotal in an IgE-mediated signaling pathway. In summary, for the first time, this study shows that 4 mu 8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4 mu 8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis. (C) 2017 Elsevier Inc. All rights reserved.