DataSheet_1_Gomisin M2 Inhibits Mast Cell-Mediated Allergic Inflammation via Attenuation of FcεRI-Mediated Lyn and Fyn Activation and Intracellular Calcium Levels.docx

Mast cells are effector cells that induce allergic inflammation by secreting inflammatory mediators. Gomisin M2 (G.M2) is a lignan isolated from Schisandra chinensis (Turcz). Baill. exhibiting anti-cancer activities. We aimed to investigate the anti-allergic effects and the underlying mechanism of G.M2 in mast cell–mediated allergic inflammation. For the in vitro study, we used mouse bone marrow–derived mast cells, RBL-2H3, and rat peritoneal mast cells. G.M2 inhibited mast cell degranulation upon immunoglobulin E (IgE) stimulation by suppressing the intracellular calcium. In addition, G.M2 inhibited the secretion of pro-inflammatory cytokines. These inhibitory effects were dependent on the suppression of FcεRI-mediated activation of signaling molecules. To confirm the anti-allergic effects of G.M2 in vivo, IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were utilized. Oral administration of G.M2 suppressed the PCA reactions in a dose-dependent manner. In addition, G.M2 reduced the ASA reactions, including hypothermia, histamine, interleukin-4, and IgE production. In conclusion, G.M2 exhibits anti-allergic effects through suppression of the Lyn and Fyn pathways in mast cells. According to these findings, we suggest that G.M2 has potential as a therapeutic agent for the treatment of allergic inflammatory diseases via suppression of mast cell activation.

肥大细胞（mast cells）是通过分泌炎性介质诱发过敏性炎症的效应细胞。戈米辛M2（Gomisin M2，简称G.M2）是从五味子（Schisandra chinensis (Turcz.) Baill.）中分离得到的木脂素类化合物，具有抗癌活性。本研究旨在探究G.M2在肥大细胞介导的过敏性炎症中的抗过敏性作用及其潜在机制。在体外实验中，我们采用了小鼠骨髓源性肥大细胞、RBL-2H3细胞以及大鼠腹腔肥大细胞。G.M2可通过抑制细胞内钙离子信号，阻断免疫球蛋白E（immunoglobulin E，IgE）刺激诱导的肥大细胞脱颗粒反应。此外，G.M2还可抑制促炎细胞因子的分泌。上述抑制效应均依赖于对FcεRI介导的信号分子活化的抑制。为验证G.M2在体内的抗过敏性作用，本研究使用了IgE介导的被动皮肤过敏反应（passive cutaneous anaphylaxis，PCA）模型与卵清蛋白诱导的主动全身过敏反应（ovalbumin-induced active systemic anaphylaxis，ASA）模型。口服给予G.M2可呈剂量依赖性抑制PCA反应。同时，G.M2可减轻ASA反应，包括降低体温、减少组胺、白细胞介素-4（interleukin-4，IL-4）及IgE的生成。综上，G.M2可通过抑制肥大细胞中的Lyn与Fyn信号通路发挥抗过敏性作用。基于上述研究结果，我们认为G.M2有望成为通过抑制肥大细胞活化治疗过敏性炎症性疾病的潜在治疗药物。