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An immunoregulatory role of nitric oxide (NO) in the development of adaptive immune responses associated with allergic diseases is very important. The present study extended these observations by the examination of the reciprocal changes in characteristic immunologic parameters of the disease and NO level of bronchoalveolar lavage (BAL) cells under guinea pig model of acute asthma with multiple challenges. Development of guinea pig Th2 mediated asthma was accompanied by increasing the level of allergic markers: ovalbumin (OVA) specific IgG and IL-4. We demonstrated that the infiltrate of airway cells contributes to NO synthesis in the respiratory tract during allergic inflammation. The level of intracellular NO formation significantly correlated with plasma allergen specific IgG value in OVA-induced asthma. The presented data evidence that the elevated intracellular NO level in BAL fluid may reflect a nitrosative stress in respiratory tract in general, when allergic asthma exacerbation is present.

The mutual association between permeability barrier dysfunction and allergic inflammation is one of the most important issues in the pathogenesis of atopic dermatitis (AD). Permeability barrier abrogation not only induces cutaneous inflammation, but is also involved in the induction of T helper 2 (Th2)-type immunological reactions. Conversely, Th2 or other cytokines abrogate permeability barrier homeostasis. Some molecules and/or pathogenic factors have been found to be simultaneously involved in both aspects of AD. Decreases in filaggrin or peroxisome proliferator-activated receptor α, which are observed in AD lesions, not only disturb the permeability barrier function but could also directly augment cutaneous inflammation via the upregulation of proinflammatory cytokines. Elevation of the stratum corneum (SC) pH, which is also observed in AD lesions, could initiate and/or drive many of the pathogenic features including both the permeability barrier disturbance and induction of Th2-type inflammation via protease-activated receptor-2-dependent and -independent mechanisms, leading to the emergence and/or exacerbation of AD. Disturbance of the SC pH recovery function is observed in flaky tail mice and might be involved in the susceptibility to AD-like dermatitis of mice with genetic abnormalities associated with permeability barrier function. Disturbed SC acidity maintenance could be regarded as a missing link that connects genetic abnormalities associated with permeability barrier dysfunction and environmental factors in the pathogenesis of AD.

Bronchial obstruction is a widespread pathological condition in children. The development of this syndrome in bronchial asthma is caused by an allergic inflammation of the mucous membranes of the respiratory tract with the participation of leukotrienes. It is found that the blocking of leukotriene receptors using the montelukast drugs has a therapeutic effect, including in children at the age of 2 and above. The drugs are well tolerated by children, can prevent a post-exertional bronchospasm and in some clinical situations can be used as an alternative to glucocorticoids.

Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. β-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as “type-2-high” (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma .

Memory T helper (mTh) cells play important roles in the reinfection of pathogens and drive the pathogenesis of diseases. While recent studies have characterized the pathogenic mTh2 cell subpopulations driving allergic inflammation, those that induce immune responses against helminth infection remain unknown. We found that IL-5- producing CXCR6+ST2+CD44+ mTh2 cells play a crucial role in the IL-33-dependent inhibition of the fecundity of helminth, whereas other ST2- mTh2 cells do not. Although both cell types induced the infiltration of granulocytes, especially eosinophils, into the lungs in response to helminth infection, the ST2+ mTh2 cell-induced eosinophils expressed higher levels of major basic protein (MBP), which is important for reducing the fecundity of Nippostrongylus brasiliensis (Nb), than ST2- mTh2 cell-induced ones. Notably, we also found that ST2+ Treg cells but not ST2- Treg cells suppressed CXCR6+ST2+ mTh2 cell-mediated immune responses. Taken together, these findings show that we identified a mechanism against helminth elicited by a subpopulation of IL-5-producing mTh2 cells through the accumulation of eosinophils strongly expressing MBP in the lungs. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Allergen specific immunotherapy (SIT) is the only specific therapeutic way for house dust mite (HDM) allergy. To improve the efficacy of SIT, hollow mesoporous silica nanoparticles (HMSNs) were used as vehicles for HDM allergen. The HMSNs were prepared and characterized. The major HDM allergen (Der f2) was loaded onto HMSNs, and the drug loading capacity and release profile were determined. Then the Der f2 loaded HMSNs were injected subcutaneously to mouse model of Der f2 induced allergic asthma and the preventive effects were evaluated. Our results showed that HMSNs were spherical (100 nm) with pore diameter of 2.897 nm and successfully loaded with Der f2 protein. The loading capacity is 90 μg Der f2/1 mg HMSNs. The Der f2 loaded on HMSNs released slowly in 72 h. Treatment with Der f2 loaded HMSNs could efficiently decrease Der f2 specific IgE levels, inflammatory cells infiltration in lung tissue, and Th2 cytokine IL4 levels in BALF. In the meanwhile, it could increase the Der f2 specific IgG levels, Th1 cytokine IFN-γ levels, and induce proliferation of splenocytes to Der f2 accompanied by increased IFN-γ levels. These results showed that Der f2 loaded HMSNs were efficient in preventing allergic inflammation, and HMSNs may be potential vehicles for SIT of HDM allergy. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Anaphylatoxin C3a and adenosine receptors (AR) are implicated in the inflammatory process associated with allergic rhinitis and asthma by modifying mast cell (MC) responses. Possible interactions between these G-protein coupled receptor (GPCR) pathways in MCs have not yet been demonstrated. LAD2 human MC were stimulated with C3a in the presence or absence of AR agonists and antagonists and their adhesion, chemotaxis and mediator release were measured. The pan-specific AR agonist, 5′-N-Ethylcarboxamidoadenosine (NECA) inhibited C3a-induced LAD2 cell migration, adhesion, degranulation, production of CCL2, and ERK1/2 phosphorylation. The selective A 2A receptor agonist CGS 21680 inhibited C3a-mediated degranulation, while the A 2B and A 3 receptor agonists BAY 60-6583 and IB-MECA, respectively, had no effect. Moreover, an A 2A receptor antagonist SCH 58261 blocked the inhibitory effect of NECA on C3a-induced degranulation, suggesting that inhibition of degranulation was mediated through the A 2A receptor. NECA increased intracellular cAMP in C3a-activated mast cells, suggesting that Gα s protein signals are required for adenosine-induced inhibition of C3a-mediated human mast cell activation. The adenylyl cyclase inhibitor SQ 22536 attenuated the inhibitory effect of NECA on C3a-activated degranulation, and the A 2A agonist CSG 21680 potentiated the inhibition of mast cell activation mediated by the A 2A receptor. Our results suggest that adenosine inhibits C3a-mediated activation of human mast cells, possibly through a Gα s protein-dependent pathway. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis (ACD) is an inflammatory skin disease caused by hapten-specific immune response. Silkworm droppings are known to exert beneficial effects during the treatment of inflammatory diseases. Here, we studied whether topical treatment and oral administration of silkworm dropping extract (SDE) ameliorate trimellitic anhydride (TMA)-induced ACD. In ACD mice model, SDE treatment significantly suppressed the increase in both ear thickness and serum IgE levels. Furthermore, IL-1β and TNF-α levels were reduced by SDE. In allergic responses, SDE treatment significantly attenuated the production of the Th2-associated cytokine IL-4 in both ear tissue and draining lymph nodes. However, it increased the production of the Th1-mediated cytokine IL-12. Thus, these results showed that SDE attenuated TMA-induced ACD symptoms through regulation of Th1/Th2 immune response. Taken together, we suggest that SDE treatment might be a potential agent in the prevention or therapy of Th2-mediated inflammatory skin diseases such as ACD and atopic dermatitis. Abbreviations: ACD: allergic contact dermatitis; AD: atopic dermatitis; APC: antigen presenting cells; CCL: chemokine (C-C motif) ligand; CCR: C-C chemokine receptor; Dex: dexamethasone; ELISA: enzyme-linked immunosorbent assay; IFN: interferon; Ig: immunoglobulin; IL: interleukin; OVA: ovalbumin; PS: prednisolone; SDE: silkworm dropping extract; Th: T helper; TMA: trimellitic anhydride; TNF: tumor necrosis factor [ABSTRACT FROM AUTHOR]

Basophils and mast cells share some features, including basophilic granules in the cytoplasm, cell surface expression of the high-affinity IgE receptor and release of chemical mediators such as histamine. Because of this similarity and their minority status, basophils had often been erroneously considered as minor relatives or blood-circulating precursors of tissue-resident mast cells, and therefore long been neglected or underestimated in immunological studies. Taking advantage of newly developed tools, such as basophil-depleting antibodies and engineered mice deficient for only basophils, recent studies have identified previously unappreciated roles for basophils, distinct from those played by mast cells, in allergic responses, protective immunity against parasitic infections and regulation of other immune cells. In this review, we focus on two topics that we presented and discussed in the 46th Annual Meeting of the Japanese Society for Immunology held in Sendai in December 2017. The first topic is the function of basophils as antigen-presenting cells for driving Th2 cell differentiation. We demonstrated that basophils produce few or no MHC class II (MHC-II) proteins by themselves although they can acquire peptide–MHC-II complexes from dendritic cells through trogocytosis, and present them and provide IL-4 to naive CD4 T cells, promoting Th2 cell differentiation. The second topic is the basophil-specific effector molecules involved in allergic responses. Among mouse mast cell proteases (mMCPs), mMCP-8 and mMCP-11 are expressed almost exclusively by basophils. Analyses in vitro and in vivo revealed that both proteases can induce leukocyte migration through distinct mechanisms, contributing to the development of basophil-dependent allergic inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Allergen‐specific immunotherapy (SIT) effectively alleviates type I allergic diseases characterized by T helper (Th)2‐type immunity. Our recent studies have shown that a synthetic trivalent glycocluster, triacedimannose (TADM), suppresses the Th2‐type allergic inflammation. The aim of this study was to compare TADM with two well‐known adjuvants, unmethylated cytosine‐phosphate‐guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen‐induced chronic allergic inflammation model in mice. Methods: Female BALB/c mice were intranasally sensitized with 50 μL of timothy grass pollen extract (TE) twice a week for a period of 15 weeks. Therapeutic intranasal treatments were then performed once a week after the tenth intranasal TE instillation using TADM (10 or 25 μg/50 μL), CpG‐ODN (20 μg/50 μL) or MPLA (2 μg/50 μL). Groups of 9‐10 animals per treatment were killed 24 hours after the last timothy dosage. Blood, bronchoalveolar lavage (BAL) fluids and lung biopsies were taken for subsequent analysis. Results: When mice were repeatedly exposed to TE for 15 weeks, the number of eosinophils and lymphocytes increased in the BAL fluids. The eosinophil and lymphocyte counts decreased dose‐dependently and were practically abolished in the mice treated with TADM. Treatments with MPLA or CpG significantly increased the number s of neutrophils, while CpG nonsignificantly decreased eosinophilia compared to timothy exposure. Conclusions: A novel synthetic glycocluster molecule inhibited the development of grass‐induced eosinophilic pulmonary inflammation in mice when administrated in the airways. This compound could be a candidate to be used either as an adjuvant in SIT or as a topical anti‐inflammatory treatment. [ABSTRACT FROM AUTHOR]

Chronic eosinophilic pneumonia (CEP) is an inflammatory disease characterized by accumulations of eosinophils in the lung with unknown etiology. Although corticosteroid treatment dramatically resolves these inflammations, relapse is common during the course of the disease. Approximately 50% of patients with CEP experience relapse. Subsequent to persistent disease and repeated relapse, and in cases of combined severe asthma, some CEP patients are administered corticosteroids indefinitely. Similar to patients with severe asthma who are often steroid dependent, a number of CEP patients exhibit prolonged persistent impairment of pulmonary function. Thus, CEP should be considered a potentially chronic disease requiring long-term management, rather than an acute or sub-acute disease requiring short-time therapy only. This review summarizes previous CEP studies, as well as our own cohort data, and discusses the long-term management of CEP with a particular focus on relapse, the prevalence of maintenance therapy, and persistent impairment of pulmonary function. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process. [ABSTRACT FROM AUTHOR]

Microbial-based cleaning products (MBCPs) contain bacteria and chemical constituents. They are used in consumer applications such as odor reduction, unclogging drains, and surface cleaning. To determine the capacity of a model MBCP to contribute to acute allergic lung inflammation, a two-week repeated exposure regimen was used. Mice were exposed by endotracheal instillation to saline alone, MBCP alone, house dust mites (HDM) alone, or sequentially (i.e., MBCP followed by HDM, HDM followed by MBCP, or HDM + MBCP followed by HDM). Both whole MBCP and acellular MBCP filtrate were investigated, and showed minimal differences in the endpoints examined. HDM exposure caused pulmonary perivascular inflammation, bronchiolar mucous cell metaplasia, elevated bronchoalveolar lavage fluid (BALF) eosinophils, and HDM-specific IgG1. For MBCP, notable changes were associated with sequential exposures. MBCP/HDM caused elevated T H 2 cytokines in BALF, and elevated neutrophils, eosinophils and IL-5 in peripheral blood. Co-administration of MBCP and HDM followed by HDM resulted in elevated blood and BALF eosinophils and HDM-specific IgE and IgG1. These results demonstrated that acellular MBCP filtrate, and not bacteria within MBCPs, potentiated the acute allergic inflammation to HDM. This methodology could be extended to investigate chronic allergic inflammation and inflammatory potential of other MBCPs and biotechnology products with complex compositions. [ABSTRACT FROM AUTHOR]

Type 2 immunopathology is a cardinal feature of allergic diseases and involves cooperation between adaptive immunity and innate effector responses. Virtually all cell types relevant to this pathology generate leukotriene and/or prostaglandin mediators that derive from arachidonic acid, express receptors for such mediators, or both. Recent studies highlight prominent functions for these mediators in communication between the innate and adaptive immune systems, as well as amplification or suppression of type 2 effector responses. This review focuses on recent advances and insights, and highlights existing and potential therapeutic applications of drugs that target these mediators or their receptors, with a special emphasis on their regulation of the innate and adaptive lymphocytes relevant to type 2 immunopathology. [ABSTRACT FROM AUTHOR]

Backgrounds: Mast cells play a major role in allergic inflammation by the release of histamine, an important mediator of type I hypersensitivity. Cencerns regarding potential harmful effects of perfluorooctane sulfonate (PFOS) have been raised. Previous studies reported that PFOS causes various adverse effects such as immunotoxicity and neurotoxicity. This report studied whether PFOS affects mast cells-mediated allergic inflammation.Methods: Ovalbumin-induced active systemic anaphylaxis model was used to assess for the type I hypersensitivity. After sensitization, mice were orally administered with PFOS and then allergic symptoms such as hypothermia and increase of serum allergic mediator were measured. In additional, this study investigated whether PFOS deteriorate allergic inflammation in immunoglobulin E-stimulated mast cells.Results: PFOS aggravated the allergic symptoms such as hypothermia, and increase of serum histamine, tumor necrosis factor-α and immunoglobulin (Ig) E/ G1. PFOS increased the release of histamine and β-hexosaminidase through the up-regulation of intracellular calcium in IgE-stimulated mast cells. PFOS also enhanced the gene expression of pro-inflammatory cytokines by activating nuclear factor-κB.Conclusion: This study demonstrated that PFOS more intensifies the mast cell-mediated allergic inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Eupatilin, a pharmacologically active ingredient found in Artemisia asiatica, has been reported to have anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, molecular mechanisms underlying its anti-allergic properties are not yet clear. In this study, we investigated the effects of eupatilin on allergic inflammation in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cells and a compound 48/80-induced anaphylactic shock model.Methods: Cytokine assays, histamine assays, quantitative real-time polymerase chain reaction analysis, western blot analysis and compound 48/80-induced anaphylactic shock model were used in this study.Results: Eupatilin significantly suppresses the expression and production of pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in vitro and in vivo. In addition, eupatilin inhibits nuclear factor kappa B (NF-κB) activation by regulating the phosphorylation and degradation of IκBα via the Akt/IKK(α/β) pathway. Eupatilin treatment also attenuates the phosphorylation of p38, ERK, and JNK MAPKs. Furthermore, eupatilin blocked anaphylactic shock and decreased the release of histamine.Conclusions: Anti-allergic inflammation may involve the expression and production of regulating pro-inflammatory cytokines via Akt/IKK(α/β) and MAPK activation of NF-κB. On the basis of these data, eupatilin is a potential candidate for the treatment of allergic diseases. [ABSTRACT FROM AUTHOR]

JNJ7777120, a histamine H4 receptor antagonist, was shown to be effective in different experimental settings of allergic inflammation, including contact hypersensitivity. Toll-like receptors (TLRs) are thought to function as a link between innate and adaptive immune responses to various haptens. Here, we studied the suppression of TLR signaling as a possible mechanism by which JNJ7777120 exerts its anti-inflammatory effects against the chemical hapten, fluorescein isothiocyanate (FITC). The potential anti-oxidant effect of JNJ7777120 in this model was also examined. Mice subjected to FITC sensitization and challenge showed significantly elevated plasma immunoglobulin E (IgE) level, ear interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), and thiobarbituric acid reactive substance (TBARS) contents as well as increased myeloid differentiation factor 88 (MyD88) gene expression, nuclear factor-kappa B p65 (NF-κB p65), and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) protein expression. This was accompanied by enhanced ear myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities as well as diminished glutathione (GSH) content and superoxide dismutase (SOD) activity. JNJ7777120 treatment perceivably reversed these effects, denoting profound anti-inflammatory and anti-oxidant character of JNJ7777120 which was confirmed by its mitigation of FITC-induced pathological changes in mouse ear. JNJ7777120 additionally enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), providing a novel mechanism by which JNJ7777120 functions as an anti-oxidant in this model. To conclude, JNJ7777120 afforded a remarkable amendment of FITC skin insult by virtue of its anti-inflammatory and anti-oxidant effects; the mechanistic basis of these effects may include modulation of TLR and Nrf2 pathways. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) represent a rapid source of type 2 cytokines, such as IL-5 and IL-13, and play an important role in orchestrating type 2 immune response. Adenosine is an endogenous purine nucleoside, a catabolite of ATP that binds and activates ≥1 of 4 transmembrane G protein-coupled cell-surface adenosine receptors (ARs)--A1, A2A, A2B, and A3. Here, we studied the role of ARs in the regulation of cytokine production by ILC2s. We found that A2BARs suppress the production of both IL-5 and IL-13 by ILC2s, whereas A2AARs augment IL-5 production and fail to affect IL-13 release. Combined stimulation of all ARs led to the suppression of both IL-5 and IL-13 production, which indicated that A2BARs dominate A2AARs. Both pre- and post-transcriptional processes may be involved in the AR modulation of ILC2 IL-5 and IL-13 production. Thus, we identify adenosine as a novel negative regulator of ILC2 activation. [ABSTRACT FROM AUTHOR]

In recent years, the bidirectional relationship between the nervous and immune system has become increasingly clear, and its role in both homeostasis and inflammation has been well documented over the years. Since the introduction of the cholinergic anti-inflammatory pathway, there has been an increased interest in parasympathetic regulation of both innate and adaptive immune responses, including T helper 2 responses. Increasing evidence has been emerging suggesting a role for the parasympathetic nervous system in the pathophysiology of allergic diseases, including allergic rhinitis, asthma, food allergy, and atopic dermatitis. In this review, we will highlight the role of cholinergic modulation by both nicotinic and muscarinic receptors in several key aspects of the allergic inflammatory response, including barrier function, innate and adaptive immune responses, and effector cells responses. A better understanding of these cholinergic processes mediating key aspects of type 2 immune disorders might lead to novel therapeutic approaches to treat allergic diseases. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILC) are a recently described group of tissue-resident immune cells that play essential roles in maintaining and protecting the tissue barrier against invading pathogens. Extensive research has revealed that ILC-mediated immune responses are controlled by dietary components and metabolites. An additional role of ILC as important direct regulators of host metabolism and glucose tolerance is emerging. This suggests that ILC may act as key dietary sensors integrating nutritional and metabolic stress to facilitate both maintenance of barrier sites and a coordinated immune response protecting these tissues. In this respect, investigations have begun to determine how different ILC responses are metabolically fueled and the impact of nutrient availability on the regulation of ILC function. Here, we discuss the current literature concerning dietary and metabolic control of ILC. In particular, we address whether the dietary and metabolic control of ILC and their simultaneous influence on host metabolism may function as a coordinated program of barrier defense. [ABSTRACT FROM AUTHOR]

Mast cell activation via the high-affinity IgE receptor (FcεRI) elicits production of inflammatory mediators central to allergic disease. As a synthetic antioxidant and a potent ribonucleotide reductase (RNR) inhibitor, Didox (3,4-dihyroxybenzohydroxamic acid) has been tested in clinical trials for cancer and is an attractive therapeutic for inflammatory disease. We found that Didox treatment of mouse bone marrow-derived mast cells (BMMC) reduced IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF and MIP-1a (CCL3). These effects were consistent using BMMC of different genetic backgrounds and peritoneal mast cells. While the RNR inhibitor hydroxyurea had little or no effect on IgE-mediated function, high concentrations of the antioxidant N-acetylcysteine mimicked Didox-mediated suppression. Furthermore, Didox increased expression of the antioxidant genes superoxide dismutase and catalase, and suppressed DCFH-DA fluorescence, indicating reduced reactive oxygen species production. Didox effects were not due to changes in FcεRI expression or cell viability, suggesting it inhibits signaling required for inflammatory cytokine production. In support of this, we found that Didox reduced FcεRI-mediated AP-1 and NFκB transcriptional activity. Finally, Didox suppressed mast cell-dependent, IgE-mediated passive systemic anaphylaxis in vivo . These data demonstrate the potential use for Didox as a means of antagonizing mast cell responses in allergic disease. [ABSTRACT FROM AUTHOR]

Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-κB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 µM) suppressed histamine release and secretion of TNF-α, IL-1β and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-κB activation and upstream IκKα phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell-mediated allergic inflammation. [ABSTRACT FROM AUTHOR]