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

Abstract

Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4μ8C, 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 4μ8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4μ8C suppressed the degranulation of IgE-mediated mast cells (IC50=3.2μM) and the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in a dose-dependent manner. 4μ8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50=25.1mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4μ8C, 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 4μ8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4μ8C 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 4μ8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4μ8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis.

• Authors: Seung Taek Nam, Young Hwan Park, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Young Mi Kim, Wahn Soo Choi
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 332 Pg. 25-31 (10 01 2017) ISSN: 1096-0333 [Electronic] United States
• PMID: 28736076 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Coumarins
• Membrane Proteins
• Tumor Necrosis Factor-alpha
• Interleukin-4
• Immunoglobulin E
• Ern2 protein, mouse
• Syk Kinase
• Syk protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Anaphylaxis (immunology)
• Animals
• Cell Degranulation (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coumarins (pharmacology)
• Dose-Response Relationship, Drug
• Hypersensitivity (drug therapy, immunology)
• Immunoglobulin E (immunology)
• Interleukin-4 (metabolism)
• Male
• Mast Cells (cytology, drug effects)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Passive Cutaneous Anaphylaxis
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Rats
• Signal Transduction
• Syk Kinase (antagonists & inhibitors, genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)