Sphingosine Kinase-1-Dependent and -Independent Inhibitory Effects ofZanthoxyliFructus to Attenuate the Activation of Mucosal Mast Cells and Ameliorate Food Allergies in Mice

Makoto Kadowaki,Natsuko Kageyama-Yahara,Takeshi Yamamoto,Shusaku Hayashi,Xiaoyu Wang

doi:10.1155/2012/862743

Makoto Kadowaki, Natsuko Kageyama-Yahara + Show 3 more

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https://doi.org/10.1155/2012/862743

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Abstract

Food allergy (FA) is relatively a common disease in infants, but effective drug therapies are not yet available. Notably, mucosal mast cells, but not connective-tissue mast cells, play important roles in food allergic reactions via the release of inflammatory mediators. Therefore, we screened medicinal herb extracts for in vitro and in vivo antiallergic activity through inhibiting mucosal mast cell activation. As a result, both antigen-induced and calcium ionophore-induced degranulation was significantly inhibited by Zanthoxyli Fructus water extract (ZF) in mucosal-type murine bone marrow-derived mast cells (mBMMCs). ZF suppressed the antigen-induced [Ca2+]i elevation and the antigen-enhanced mRNA expression of TNF-α, IL-4, and IL-13. The transcriptome and real-time PCR analyses revealed that ZF greatly decreased the antigen-enhanced expression level of sphingosine kinase 1 (Sphk1), which plays a key role in the FcεRI-mediated immune responses in mast cells. Furthermore, ZF inhibited allergic symptoms in an ovalbumin-caused murine FA model and decreased the number of infiltrating mucosal mast cells and the enhanced mRNA expression levels of IL-4 and Sphk1 in the FA mice colons. These results indicate that ZF suppresses mucosal mast cell activities mainly through Sphk1-dependent mechanism, and ZF is utilized for the development of a novel, potent anti-FA agent.

Highlights

Food allergy (FA) is an abnormal immunologic reaction to food proteins
We investigated the effect of the water extract of the fruit of Zanthoxylum piperitum De Candolle (ZPDC) (ZF) on mucosal mast cells, explored the underlying mechanism of the pharmacological effects, and demonstrated for the first time that Zanthoxyli Fructus water extract (ZF) inhibited the activation of mucosal mast cells in vitro and in vivo primarily through the suppression of antigen-induced sphingosine kinase 1 (Sphk1) gene expression
To investigate the pharmacological profile of ZF on mucosal mast cell activation, we examined the effect of ZF on the [Ca2+]i increases and β-hexosaminidase release induced by the calcium ionophore A23187

Summary

Introduction

Food allergy (FA) is an abnormal immunologic reaction to food proteins. The prevalence of FA in children is estimated to be approximately 4% to 10%. Connective tissue mast cell stabilizers (tranilast, ketotifen, and cromolyn) are frequently used for the treatment of various allergic disorders besides FA These agents have no effect on mucosal mast cells [8]. It has been reported that glycoproteins in the Zanthoxyli Fructus have anti-inflammatory properties [16] It remains still unclear whether Zanthoxyli Fructus plays a suppressive effect on the activation of mucosal mast cells and the development of FA. We investigated the effect of the water extract of the fruit of ZPDC (ZF) on mucosal mast cells, explored the underlying mechanism of the pharmacological effects, and demonstrated for the first time that ZF inhibited the activation of mucosal mast cells in vitro and in vivo primarily through the suppression of antigen-induced sphingosine kinase 1 (Sphk1) gene expression. ZF may serve as a leading candidate for the development of novel anti-FA agents

Materials and Methods

Results

Discussion

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A23187