Sauchinone suppresses FcεRI-mediated mast cell signaling and anaphylaxis through regulation of LKB1/AMPK axis and SHP-1-Syk signaling module

• Published in: International immunopharmacology 2019-09, Vol.74, p.105702-105702, Article 105702
• Main Authors: Deng, Yifeng, Jin, Fansi, Li, Xian, Park, Sung Joon, Chang, Jae-Hoon, Kim, Dong-Young, Kim, Jung-Ae, Nam, Joo-Won, Choi, Hyukjae, Lee, Youn Ju, Chang, Hyeun Wook
• Format: Article
• Language: English
• Subjects: Adenosine monophosphate-activated protein kinase; AKT protein; Allergy; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Anaphylaxis; Anaphylaxis - drug therapy; Animals; Anticancer properties; Antioxidants; Biological activity; Bone marrow; Calcium (intracellular); Calcium ions; Cell activation; Cells, Cultured; Chemical compounds; Cytokines; Degranulation; Disease Models, Animal; Eicosanoids; Homology; Humans; Hypersensitivity - drug therapy; Immunoglobulin E; Inflammatory diseases; Intracellular signalling; Kinases; LKB1 protein; Lymphocytes; Lymphocytes T; Mast cell; Mast cells; Mast Cells - physiology; Medical treatment; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Passive cutaneous anaphylaxis; Pharmacology; Phospholipase; Phospholipase C; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Protein-Serine-Threonine Kinases - metabolism; Protein-tyrosine-phosphatase; Proteins; Receptors, IgG - metabolism; Sauchinone; SHP-1 protein; Signal Transduction; Signaling; siRNA; Src homology 2 domain-containing phosphatase-1; Syk Kinase - metabolism; Syk protein; Tyrosine
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.105702

Sauchinone, the biologically active lignan of Saururus chinensis, has been reported to have anti-inflammatory, antitumor, antioxidant, and hepatoprotective properties. However, little is known about the effect of sauchinone on FcεRI-mediated mast cell activation. The aim of this study was to evaluate the anti-allergic activity of sauchinone and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and the mast cell-mediated passive cutaneous anaphylaxis (PCA) model. Sauchinone markedly suppressed FcεRI-mediated activation of positive signaling mediators, including Syk, linker for activation of T cells (LAT), phospholipase C (PLC)γ, mitogen-activated protein (MAP) kinases, Akt, IκB kinase (IKK), and intracellular Ca2+, and increased the activation of negative signaling mediators, including liver kinase B (LKB)1/AMP-activated protein kinase (AMPK) and Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1. Interestingly, sauchinone increased the interaction between SHP-1 and Syk. Consequently, sauchinone significantly suppressed FcεRI-mediated BMMC degranulation and synthesis of eicosanoids and cytokines. These inhibitory effects of sauchinone were diminished in BMMCs treated with siRNAs targeting LKB1, AMPKα2, or SHP-1, and in BMMCs isolated from AMPKα2-deficient mice. In addition, administration of sauchinone markedly suppressed the IgE-mediated PCA reaction in wild-type mice, and this inhibitory effect was significantly reduced in AMPKα2−/− mice. Taken together, these data suggest that sauchinone suppresses FcεRI-mediated mast cell activation and anaphylaxis through modulation of the LKB1/AMPK and SHP-1/Syk pathways. Therefore, sauchinone might be a potential therapeutic agent for the treatment of allergic inflammatory diseases. •Sauchinone inhibits IgE-mediated mast cell activation and anaphylaxis.•Sauchinone suppresses allergic responses via modulating LKB1/AMPK and SHP-1/Syk.•Interaction between SHP-1 and Syk by sauchinone inhibits Syk phosphorylation.•Sauchinone is a potential therapeutic agent for mast cell-dependent allergic diseases.