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(1) Background: This study aims to elucidate a novel non-transcriptional action of IRF3 in addition to its role as a transcription factor in mast cell activation and associated allergic inflammation; (2) Methods: For in vitro experiments, mouse bone-marrow-derived mast cells (mBMMCs) and a rat basophilic leukemia cell line (RBL-2H3) were used for investigating the underlying mechanism of IRF3 in mast-cell-mediated allergic inflammation. For in vivo experiments, wild-type and Irf3 knockout mice were used for evaluating IgE-mediated local and systemic anaphylaxis; (3) Results: Passive cutaneous anaphylaxis (PCA)-induced tissues showed highly increased IRF3 activity. In addition, the activation of IRF3 was observed in DNP-HSA-treated mast cells. Phosphorylated IRF3 by DNP-HSA was spatially co-localized with tryptase according to the mast cell activation process, and FcεRI-mediated signaling pathways directly regulated that activity. The alteration of IRF3 affected the production of granule contents in the mast cells and the anaphylaxis responses, including PCA- and ovalbumin-induced active systemic anaphylaxis. Furthermore, IRF3 influenced the post-translational processing of histidine decarboxylase (HDC), which is required for granule maturation; and (4) Conclusion: Through this study, we demonstrated the novel function of IRF3 as an important factor inducing mast cell activation and as an upstream molecule for HDC activity. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA) has wide applications, including as a raw material for converted paper and packaging products. With the widespread use of PFOA, concerns regarding its potential environmental and health impacts have increased. In spite of the known hepatotoxicity and genotoxicity of PFOA, correlation with PFOA and allergic inflammation is not well known. In this study, the effect of PFOA on the degranulation of mast cells and mast cell-mediated allergic inflammation in the presence of FcεRI cross-linking was evaluated. In immunoglobulin (Ig) E-stimulated mast cells, PFOA increased the release of histamine and β-hexosaminidase by the up-regulation of intracellular calcium levels. PFOA enhanced gene expression of several pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 by the activation of nuclear factor (NF)-κB in IgE-stimulated mast cells. Also, PFOA exacerbated allergic symptoms via hypothermia, and an increase of serum histamine, TNF-α, IgE and IgG1 in the ovalbumin-induced systemic anaphylaxis. The present data indicate that PFOA aggravated FcɛRI-mediated mast cell degranulation and allergic symptoms. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

• Dabrafenib inhibited IgE-induced mast cell activation. • Dabrafenib decreased the activity of signaling molecules (Lyn, Syk, Akt, and PLCγ). • Dabrafenib reduced IL-4 and TNF-α by the inhibition of NF-κB and NFAT. • Dabrafenib ameliorated mast cell-mediated local anaphylaxis. The functional inhibition of mast cells, which serve as a key effector cells in allergic reactions may be a specific target for treating immunoglobulin (Ig)E-mediated allergic reactions, which occur in various allergic diseases including anaphylaxis, asthma, and atopic dermatitis. In this study, we demonstrated the effects of dabrafenib, a therapeutic agent used to treat metastatic melanoma, with a focus on mast cell activation and local cutaneous anaphylaxis. In two types of mast cells (RBL-2H3 and mouse bone marrow-derived mast cells), dabrafenib (0.01, 0.1, 1 μM) pretreatment significantly decreased IgE-induced degranulation, intracellular calcium influx, and the activity of intracellular signaling molecules, such as Lyn, Syk, Akt, and PLCγ. Dabrafenib ameliorated mRNA and protein expression levels of interleukin-4 and tumor necrosis factor-α by the reduction of nuclear localization of nuclear factor-κB and nuclear factor of activated T-cells. In passive cutaneous anaphylaxis, oral administration of dabrafenib (0.1, 1, 10 mg/kg) reduced local pigmentation and ear thickness in a dose-dependent manner. Taken together, these results suggest that dabrafenib is a therapeutic drug candidate that controls IgE-mediated allergic inflammatory diseases through suppression of mast cell activity. [ABSTRACT FROM AUTHOR]

Abstract Mast cells play a major role in immunoglobulin E-mediated allergic inflammation, which is involved in asthma, atopic dermatitis, and allergic rhinitis. Nothofagin has been shown to ameliorate various inflammatory responses such as the septic response and vascular inflammation. In this study, we assessed the inhibitory effect of nothofagin on allergic inflammation using cultured/isolated mast cells and an anaphylaxis mouse model. Nothofagin treatment prevented histamine and β-hexosaminidase release by reducing the influx of calcium into the cytosol in a concentration-dependent manner. Nothofagin also inhibited the gene expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-4 by downregulating the phosphorylation of Lyn, Syk, Akt and nuclear translocation of nuclear factor-κB. To confirm these effects of nothofagin in vivo , we used a passive cutaneous anaphylaxis mouse model. Topical administration of nothofagin suppressed local pigmentation and ear thickness. Taken together, these results suggest nothofagin as a potential candidate for the treatment of mast cell-involved allergic inflammatory diseases. Highlights • Nothofagin suppressed IgE-induced mast cell degranulation. • Nothofagin downregulated NF-κB translocation through blocking calcium influx. • Nothofagin attenuates vascular permeability induced by mast cell degranulation. • Nothofagin could be used to ameliorate allergic inflammation. [ABSTRACT FROM AUTHOR]

• UA inhibited mast cell degranulation by reducing intracellular calcium level. • UA attenuated secretion of pro-inflammatory cytokines in mast cells. • These effects of UA were dependent on inhibition of FcεRI-mediated signaling. • UA suppressed the local and systemic anaphylactic reactions. • UA might be a potential candidate for the treatment of allergic diseases. Mast cells are the primary cells that play a crucial role in the allergic diseases via secretion of diverse allergic mediators. Ursolic acid (UA) is a naturally occurring anti-inflammatory triterpenoid possessing various biological properties such as immune regulation, antioxidant, and anti-fibrotic. The aim of this study was to evaluate the effects of UA in FcεRI-mediated mast cell activation and allergic inflammation. In this study, mast cells were stimulated with immunoglobulin E (IgE) and the anti-allergic effects of UA were assessed by measuring the levels of allergic mediators. In vivo effects of UA were observed by generating passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) in mouse model. We found that UA inhibited the degranulation of mast cell by suppressing the intracellular calcium level in a concentration-dependent manner. UA inhibited the expression and the release of pro-inflammatory cytokines in mast cells. Anti-allergic effects of UA were demonstrated via suppression of FcεRI-mediated signaling molecules. In addition, UA inhibited the IgE-mediated PCA and ovalbumin-induced ASA reactions in a dose-dependent manner. Based on these findings, we suggest that UA might have potential as a therapeutic candidate for the treatment of allergic inflammatory diseases via inhibition of FcεRI-mediated mast cell activation. [ABSTRACT FROM AUTHOR]

A promising approach to treat a variety of diseases are considered as complementary and alternative herbal medicines. Prunus serrulata var. spontanea L. (Rosaceae) is used as herbal medicine to treat allergic diseases according to the Donguibogam, a tradition medical book of the Joseon Dynasty in Korea. We prepared the aqueous extract of the bark of P. serrulata (AEBPS) and aimed to investigate the effects in mouse anaphylaxis models and various types of mast cells, including RBL-2H3, primary cultured peritoneal and bone marrow-derived mast cells. We used ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and immunoglobulin (Ig) E-mediated passive cutaneous anaphylaxis (PCA) models, in vivo. The control drug dexamethasone (10 mg/kg) was used to compare the effectiveness of AEBPS (1–100 mg/kg). In vitro , IgE-stimulated mast cells were used to confirm the role of AEBPS (1–100 μg/mL). For statistical analyses, p values less than 0.05 were considered to be significant. In ASA model, oral administration of AEBPS suppressed the hypothermia and increased level of serum histamine in a dose-dependent manner. AEBPS attenuated the serum IgE, OVA-specific IgE, and interleukin (IL)-4. Oral administration of AEBPS also blocked mast cell-dependent PCA. AEBPS suppressed degranulation of mast cells by reducing intracellular calcium level in mast cells. AEBPS inhibited tumor necrosis factor-α and IL-4 expression and secretion in a concentration-dependent manner through the reduction of nuclear factor-κB. On the basis of these findings, AEBPS could serve as a potential therapeutic target for the management of mast cell-mediated allergic inflammation and as a regulator of mast cell activation. Image 1 [ABSTRACT FROM AUTHOR]

As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides . TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo , the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Extracts from various parts of Ampelopsis brevipedunculata has been used as anti-inflammatory agents in Asian folk medicine. Aim of the study : To demonstrate the medicinal effect of the A. brevipedunculata in skin inflammation, specifically atopic dermatitis (AD). The effect of ethanol extract of A. brevipedunculata rhizomes (ABE) on AD was examined using an AD-like skin inflammation model induced by repeated exposure to house dust mite (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB). The mechanism study was performed using tumor necrosis factor (TNF)-α and interferon (IFN)-γ-activated human keratinocytes (HaCaT). Serum histamine and immunoglobulin levels were quantified using enzymatic kits, while the gene expression of cytokines and chemokines was analyzed using quantitative real time polymerase chain reaction. The expression of signaling molecules was detected using Western blot. Oral administration of ABE alleviated DFE/DNCB-induced ear thickening and clinical symptoms, as well as immune cell infiltration (mast cells and eosinophils) into the dermal layer. Serum Immunoglobulin (Ig) E, DFE-specific IgE, IgG2a, and histamine levels were decreased after the administration of ABE. ABE also inhibited CD4+IFN-γ+ and CD4+IL-4+ lymphocyte polarization in lymph nodes and expression of TNF-α, IFN-γ, IL-4, IL-13, and IL-31 in the ear tissue. In TNF-α/INF-γ-stimulated keratinocytes, ABE inhibited the gene expression of TNF-α, IL-6, IL-1β, and CCL17. In addition, ABE decreased the nuclear localization of signal transducer and activator of transcription 1 and nuclear factor-κB, and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Collectively, our data demonstrate the pharmacological role and signaling mechanism of ABE in the regulation of skin allergic inflammation, which supports our suggestion that ABE could be developed as a potential therapeutic agent for the treatment of AD. Image 1 [ABSTRACT FROM AUTHOR]