Effects of Syo-seiryu-to and Its Constituent Crude Drugs on Phorbol Ester-Induced Up-Regulation of IL-33 and Histamine H1 Receptor mRNAs in Swiss 3T3 and HeLa Cells

Abstract

Syo-seiryu-to (SST) is a traditional herbal medicine that has been used clinically to treat allergic rhinitis (AR) in Japan. SST improves acute symptoms, such as sneezing and rhinorrhea, as well as chronic symptoms, such as nasal obstruction, in patients with AR. However, its therapeutic mechanisms remain unknown. We examined the effects of SST and eight constituent crude drugs on phorbol 12-myristate-13-acetate (PMA)-induced gene up-regulation of IL-33 and histamine H1 receptor (H1R), which are responsible for the pathogenesis of AR. We found that SST and its crude drugs, except for Pinellia tuber, significantly and dose-dependently suppressed PMA-induced both IL-33 and H1R mRNA up-regulation in vitro. The half-maximal inhibitory concentration values of the seven crude drugs to inhibit PMA-induced IL-33 mRNA up-regulation were correlated with those related to H1R mRNA up-regulation, suggesting that they act on a common signal molecule. These results suggest that SST improves nasal congestion that is induced by IL-33-related eosinophil infiltration and inhibits sneezing and rhinorrhea that are induced by H1R-mediated histamine signaling in the nasal mucosa of AR patients through its inhibition of a common molecule in the gene expression pathways of IL-33 and H1R. The results could explain the advantages of traditional herbal medicine, in which mixing various crude drugs not only acts on a common target to enhance its pharmacological action, similar to the effect of a high concentration of a single crude extract but also has the benefit of reducing the side effects of each crude drug.

Betuletol, a Propolis Component, Suppresses IL-33 Gene Expression and Effective against Eosinophilia

“…As shown in Figure 1 , the ethanolic extract of freeze-dried powder of Brazilian green propolis (BGP) was fractionated using various solvents; the suppressive activity of each fraction was examined using PMA-induced up-regulation of IL-33 gene expression in Swiss 3T3 cells using our previously established procedure [ 5 , 6 ]. The chloroform fraction exhibited the highest activity; this fraction was further fractionated by silica gel column chromatography, followed by Sephadex LH-20 column, resulting in the isolation of an active molecule.…”

“…We have isolated several flavonoids and studied their antiallergic properties, including quercetin, epigallocatechin-3- O -gallate from green tea extract [ 42 , 43 ], and (−)-maackiain from Sophora root ( Sophora flavescens ) extract [ 44 ]. These compounds suppressed IL-33 gene expression through the inhibition of both PKCδ phosphorylation and followed by ERK phosphorylation with IC 50 values of ~10 µg/mL [ 6 ], but betuletol inhibits only ERK phosphorylation, suggesting a specific and noble mechanism for IL-33 gene suppression. The IC 50 values of quercetin and maackiain were lower than that of betuletol.…”

“…Eosinophils play a major role in chronic symptoms of allergy [ 3 , 4 ]. Our study indicates that Interleukin (IL)-33 is an allergy-sensitive gene to eosinophilic inflammation and found that the levels of eosinophils were correlatively promoted with nasal mucosal IL-33 mRNA levels in pollinosis patients, indicating that the activation of IL-33 gene expression participates in eosinophilia [ 5 , 6 ]. IL-33 is required in the pathogenesis of AR through the induction of Th2 cytokines and eosinophils and could be controlled by suppressing IL-33 gene expression [ 7 , 8 ].…”

Shoseiryuto Ameliorated TDI-Induced Allergic Rhinitis by Suppressing IL-33 Release from Nasal Epithelial Cells

“…SST seems to affect the step of the infiltration of mast cells and eosinophils into the nasal mucosa in AR development [ 28 , 29 ]. Nakano et al showed that SST suppressed phorbol ester-induced increase of IL-33 and histamine H1 receptors in cultured Swiss 3T3 and HeLa Cells [ 30 ]. In addition to these reported functions of SST, our study would raise a possible mechanism underlying how SST ameliorates symptoms of AR patients as inhibition of IL-33 release from nasal epithelial cells stimulated by allergens.…”