Shuang-Huang-Lian prevents basophilic granulocyte activation to suppress Th2 immunity

Qiaoling Fei,Rui Hou,Yun Qi,Yixin Han,Ruijuan Qi,Yuan Gao,Runlan Cai,Lei Fang

doi:10.1186/s12906-017-2071-y

Abstract

BackgroundBasophilic granulocytes (BGs) not only initiate the induction of Th2 cell differentiation, but also amplify the ongoing Th2 response. Shuang-Huang-Lian (SHL) is clinically used for relieving type I hypersensitivity by continuous treatment for several weeks.MethodsELISA, flow cytometry, magnetic activated cell sorting, isoelectric precipitation, hybridoma technique, transfection and luciferase reporter assay were used in this study. The statistical analysis was performed using a one-way ANOVA.ResultsOur recently published study demonstrated that SHL exerted a remarkable effect on mast cell stabilization. Herein, we sought to elucidate the effect of SHL on shrimp tropomyosin (ST)-induced Th2 immunity and its underlying mechanisms. The obtained data showed that continuous treatment with SHL significantly suppressed ST-stimulated Th2-cytokines release and IgE synthesis. A mechanistic study indicated that SHL not only reduced BG early IL-4 release before ST-specific IgE (sIgE) production, but also inhibited BG activation in the presence of sIgE, including suppressing CD200R surface expression and decreasing IL-4 production. Moreover, SHL markedly decreased the cytosolic Ca2+ (Ca2+[c]) level and inhibited the nuclear factor of activated T cells (NFAT) activation in RBL-2H3 cells.ConclusionsCollectively, SHL potently reduces ST-induced Th2 immunity by inhibiting the BG Ca2+-NFAT pathway and, thus, suppressing the early IL-4 release before sIgE synthesis and inhibiting BG activation in the presence of sIgE. This study provides the pharmacological basis for the clinical use of SHL to relieve type I hypersensitivity by a successive dose regimen.

Highlights

Basophilic granulocytes (BGs) initiate the induction of Th2 cell differentiation, and amplify the ongoing Th2 response
SHL suppresses Th2 cytokine production by splenocytes from the shrimp tropomyosin (ST)-sensitized mice As shown in Fig. 2, in vitro ST stimulation significantly increased the release of IL-4, IL-5, IL-10 and IL-13 but simultaneously decreased IFN-γ secretion
This suppressive effect of SHL on Th2 immunity is attributed to its inhibition of BG activation, including suppressing CD200R surface expression and decreasing IL-4 production, in the early or middle/late stage

Summary

Introduction

Basophilic granulocytes (BGs) initiate the induction of Th2 cell differentiation, and amplify the ongoing Th2 response. Naïve CD4+ T (NCT) cells, known as T-helper (Th) cells, play critical roles in orchestrating adaptive immune responses to a variety of pathogens. They are involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. Unlike Th1 immunity, in which dendritic cells (DCs) present antigens and produce Th1-inducing cytokines, such as IFN-γ (and, in humans, by type I IFN [5]), DCs fail to produce IL-4, the key driver of CD4+ Th2 cell responses. The induction of Th2 responses may require an alternative (non-DC) antigen-presenting cell (APC). Many studies have suggested that BG-derived IL-4 is crucial for promoting Th2 skewing upon cysteine proteases, allergens and extracellular parasites [9, 11], and BGs trump DCs as APCs for Th2 responses [12]

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