Plant-Derived Molecule 4-Methylumbelliferone Suppresses FcεRI-Mediated Mast Cell Activation and Allergic Inflammation

Abstract

Mast cells (MCs) are an important treatment target for high-affinity IgE Fc receptor (FcεRI)-mediated allergic diseases. The plant-derived molecule 4-methylumbelliferone (4-MU) has beneficial effects in animal models of inflammation and autoimmunity diseases. The aim of this study was to examine 4-MU effects on MC activation and probe the underlying molecular mechanism(s). We sensitized rat basophilic leukemia cells (RBLs) and mouse bone marrow-derived mast cells (BMMCs) with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated them with exposure to DNP-human serum albumin (HSA), and then treated stimulated cells with 4-MU. Signaling-protein expression was determined by immunoblotting. In vivo allergic responses were examined in IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) mouse models. 4-MU inhibited β-hexosaminidase activity and histamine release dose-dependently in FcεRI-activated RBLs and BMMCs. Additionally, 4-MU reduced cytomorphological elongation and F-actin reorganization while down-regulating IgE/Ag-induced phosphorylation of SYK, NF-κB p65, ERK1/2, p38, and JNK. Moreover, 4-MU attenuated the PCA allergic reaction (i.e., less ear thickening and dye extravasation). Similarly, we found that 4-MU decreased body temperature, serum histamine, and IL4 secretion in OVA-challenged ASA model mice. In conclusion, 4-MU had a suppressing effect on MC activation both in vitro and in vivo and thus may represent a new strategy for treating IgE-mediated allergic conditions.

Formononetin Inhibits Mast Cell Degranulation to Ameliorate Compound 48/80-Induced Pseudoallergic Reactions

“…Toluidine blue or F-actin staining can reveal MC morphology and the release of heterochromatin particles that is characteristic of MC activation [ 12 ]. Pretreatment with FNT reduced the appearance of irregularly shaped cells and of cytoplasmic purple particles in RBL-2H3 following C48/80 stimulation ( Figure 2 A,B).…”

“…RBL-2H3 cells were fixed with paraformaldehyde and stained with toluidine blue solution as described previously [ 12 ]. The heterochromatic particles in the stained cells were observed using an inverted microscope (Carl Zeiss, Goettingen, Germany).…”

Inhibitory Effects of Grewia tomentosa Juss. on IgE-Mediated Allergic Reaction and DNCB-Induced Atopic Dermatitis

“…The high-affinity IgE receptor FcεRI is expressed on the surfaces of mast cells, and crosslinked IgE–FcεRI complexes are induced when a multivalent antigen binds to IgE bound to FcεRI [ 6 ]. Activation of the IgE/FcεRI pathway gives rise to mast cell degranulation and promotes the secretion of mediators that induce allergic reactions [ 7 ]. Because the secretion of these mediators also leads to inflammation, a method to inhibit the activation of mast cells could help to treat allergic symptoms.…”