IgE-mediated Histamine Release Research Articles

Ameliorative potential of galangin in murine model of ovalbumin-induced allergic rhinitis: a role of PI3K-PKB pathway.

To examine the potential of galangin in a mouse model of ovalbumin (OVA)-induced allergic rhinitis (AR), as chronic AR, induced by immunoglobulin-E (IgE), leads to histamine release and nasal inflammation, and although galangin exhibits antiasthmatic and anti-inflammatory potential, its effect on AR is yet to be investigated. 126 BALB/c mice. AR induction involved sensitizing female mice with OVA (5%, 500 µL, IP) for 14 days. Post OVA challenge, the mice were divided into 7 groups (n = 18/group), including normal, AR control, montelukast (10 mg/kg), galangin (5, 10, and 20 mg/kg), and per se (galangin [20 mg/kg] treatment. Various outcomes were evaluated, including nasal symptoms, histopathology, biochemistry, and nasal lavage fluid inflammatory cytokines and signaling pathways in nasal mucosal to assess galangin potential in AR. In AR mice, galangin (10 and 20 mg/kg) significantly (P < .05) reduced sneezing, rubbing, and nasal discharge post-OVA challenge. Galangin treatment attenuated (P < .05) elevated serum histamine, β-hexosaminidase, IgE, and Immunoglobulin G1 levels in AR control mice. Additionally, galangin significantly (P < .05) decreased OVA-induced alterations in IL-4, IL-6, IL-13, and interferon-γ levels in nasal lavage fluid compared to AR control mice. Western blot analysis demonstrated that galangin lowered OVA-induced AR by significantly (P < .05) downregulating the phosphorylated protein kinase B and mammalian target of rapamycin-protein expressions while markedly (P < .05) upregulating the glycogen synthase kinase-3β protein expressions in nasal mucosal. Galangin also significantly ameliorated (P < .05) the OVA-induced histological aberrations in the nasal mucosa, reflected by reduced eosinophil infiltration, hyperplasia, and edema. Galangin exhibits antihistaminic and anti-inflammatory effects in AR mice by regulating IgE-mediated histamine and inflammatory release and modulating the phosphatidylinositol 3-kinase/Ak strain transforming/mammalian target of rapamycin pathways.

Androgen Receptor Deficiency Eliminates Sex Differences in Mast Cells

Abstract A sex bias exists in mast cell (MC)-associated inflammatory diseases with females at increased risk. Our previous studies demonstrated that MCs exhibit a sexually dimorphic phenotype with male MCs exhibiting significantly reduced concentration and release of MC granule mediators (histamine, serotonin, and proteases) which was associated with reduced severity of anaphylaxis in males. Further, we showed that perinatal androgens are important in organizing male MC sex differences. The mechanisms by which androgens organize MC sex differences remain poorly understood. Utilizing male mice with reduced androgen receptor (AR) expression induced by Cre-LoxP technology (induced TFM; iTfm), we tested the hypothesis that ARs mediate sex differences in MC histamine storage and release, and severity of anaphylaxis. Isolated peritoneal MCs (pMCs) from iTFm male mice exhibited a feminized MC phenotype characterized by a greater level of histamine compared with control male pMCs, but similar to female controls. Following induction of IgE-mediate anaphylaxis in vivo, iTFM male and female pMCs contained lower (n=5–6; P&amp;lt;0.01) histamine contents compared with control males, suggesting enhanced release of histamine. Preliminary results also indicate that iTFm male mice exhibit greater IgE-mediated histamine releases and hypothermia. Experiments with bone marrow derived MCs (BMMCs) showed that IgE-mediated histamine release from iTFm male and female BMMCs was greater (n=5–6; P&amp;lt;0.01) relative to control male BMMCs. Together, these studies demonstrate that sex differences in MC phenotype and function are mediated via Ars and that iTFm mice are a valid model to explore AR-mediated sex differences in MC function and disease pathogenesis. Supported by NIH R01 HD072968, NIH R21 AI140413

Early life adversity programs a hyperactive mast cell phenotype and induces long-lasting changes in the mast cell transcriptome

Abstract Early life adversity (ELA) induces long-lasting chronic low-grade immune activation and increases the risk for inflammatory and metabolic disorders later in life. Our previous studies demonstrated that mast cells (MCs) which are well-established orchestrators of immune responses and as effector cells of the stress response exhibit heightened reactivity to later life stressors. Here, we used a murine model of ELA (neonatal maternal separation + early weaning; NMSEW) to determine the long-lasting programming effects of ELA on MC phenotype and function. Bone marrow-derived mast cells (BMMCs) from adult female NMSEW mice exhibited greater IgE-mediated histamine release and LPS- and IL33-induced cytokines release, compared with normally handled (NH) control mice. RNA sequencing of BMMCs from adult NH and NMSEW female mice, followed by gene pathway analysis using Ingenuity Pathway Analysis, revealed significant alterations in gene expression associated with cell migration and trafficking, glycolysis and TCA cycle regulation, lipid and cholesterol synthesis, and toll like receptor signaling. Ongoing experiments aim to characterize the long-lasting metabolic alterations induced by NMSEW through functional assays and protein expression analysis. Understanding how ELA programs MCs could identify the cellular mechanisms driving persistent MC hyper-activation and related risk for inflammatory diseases. Supported by grants from NIH/NICHD (R01 HD072968), NIH/NIAID (R01 AI152268), and USDA (USDA-NIFA 2019-67015-29483).

Perioperative anaphylaxis to intravenous vancomycin in a pediatric patient with previous topical exposures

Vancomycin is a glycopeptide antibiotic often implicated in hypersensitivity reactions. Immunoglobulin E (IgE)–mediated anaphylaxis to vancomycin is rare, and vancomycin is more frequently described as causing “red man syndrome”—characterized by immediate-onset erythema, pruritus, and sometimes hypotension—secondary to non–IgE-mediated histamine release (ie, by Mas-related G protein-coupled receptor-X2).1,2 A recent systematic review of vancomycin hypersensitivity identified only 7 cases of presumed IgE-mediated reactions, none of whom were children.

Revisiting the role of MRGPRX2 on hypersensitivity reactions to neuromuscular blocking drugs.

Anaphylaxis is caused by a variety of triggers including Food and Drug Administration (FDA)-approved antibiotics, contrast media and neuromuscular blocking drugs (NMBDs). Traditionally, drug-induced anaphylaxis was thought to result mainly from IgE-mediated histamine release from mast cells. Recently, a G protein-coupled receptor known as MRGPRX2 has been identified and shown to be highly expressed on human skin but not lung mast cells. The demonstration that many NMBDs induce degranulation in human mast cells via MRGPRX2 led to the idea that this receptor contributes to NMBD-induced hypersensitivity reactions. However, other studies have raised doubts regarding its role in drug-induced hypersensitivity. This review discusses the current status and controversy on MRGPRX2's role on NMBD-induced hypersensitivity.

Response of peripheral blood basophils in subjects with chronic spontaneous urticaria during treatment with omalizumab

Treatment of patients with asthma or food allergy with omalizumab results in several consistent changes in circulating basophils. The multiple basophil phenotypes observed in patients with chronic spontaneous urticaria (CSU) present some unique attributes that may not respond in a similar fashion to patients with asthma or food allergy. As part of a clinical study on the therapeutic outcomes of omalizumab treatment in CSU, the basophil compartment was examined for changes in characteristics predicted by prior studies. This study sought to examine the changes in basophil function and its relationship to auto-antibodies in serum during treatment with omalizumab. At multiple time points before and during omalizumab treatment of patients with CSU, basophil surface IgE and FcεRI expression, cellular spleen tyrosine kinase (SYK) expression, IgE-mediated histamine release (HR), and the presence of auto-antibodies in serum were determined. Three basophil phenotypes were enumerated in the clinical study and used to group results in this basophil study: subjects with (1) basopenia, (2) normal basophil numbers with normal IgE-mediated HR, and (3) normal basophil numbers with poor HR. Basopenia was highly associated with the presence of auto-antibodies to unoccupied FcεRI and basophil numbers did not change during treatment. Likewise, subjects who are basopenic showed no changes in SYK expression or HR during treatment. In basophils of subjects who are nonbasopenic, increases in SYK expression and HR showed the expected inverse relationship to starting SYK and HR levels. Treatment with omalizumab resulted in similar kinetics for decreases in surface FcεRI and IgE in all 3 groups. A unifying interpretation of the results revolves around the presence of auto-antibodies to FcεRI in CSU. If present, basopenia and an absence of changes in basophils during omalizumab treatment are observed. If auto-antibodies are absent, the changes in the basophil compartment are consistent with prior studies of asthma and food allergy. These group differences also are related to efficacy of the treatment for clinical outcomes, as found in the parent clinical study.

Skin Lesions with An Odontogenic Origin

Dermatological disorders have an alarming incidence of 60% in the Indian scenario. These disorders can range from mild dermatitis, acne to the most severe form of unresolving urticaria, pruritis etc. Clinicians have come a long way in terms of advancements in the diagnosis and management of these lesions. However, infection including dental infection, as a common source of etiology for such dermatological disorders is often neglected. Common sources of infection from the orofacial region include periodontitis, partially impacted teeth, periapical lesions, and so on. The probable mechanism supporting this mysterious correlation is of hematogenous spread of infection/bacteria and IgE mediated histamine release thereby, triggering and causing dermatological lesions. Here, we report 2 such cases of chronic urticaria which resolved on dental therapy

Early Life Adversity Programs Mast Cells Toward a Hyperactive Phenotype into Adulthood

Abstract Early life adversity (ELA) is a risk factor in the onset and exacerbation of inflammatory disorders including allergy, asthma and chronic pain disorders such as irritable bowel syndrome (IBS). Our previous studies using murine and porcine models showed that mast cells (MCs), a key immune cell driving allergies and chronic pain disorders, display a hyperactive tissue phenotype in adult animals exposed to ELA. The mechanism by which ELA induces MC hyperactivity in adulthood remains unknown. The aim of this study was to determine if ELA programs bone marrow derived MC progenitors toward a hyperactive phenotype into adulthood by using an ELA model of neonatal maternal separation plus early weaning (NMSEW). Female pups (C57BL/6) were either raised normal handled (NH) or NMSEW. At 10 weeks, serum and mesenteric windows from jejunum were collected to evaluate histamine and tissue MC activation. Bone-marrow derived MCs (BMMCs) from mice were harvested and stimulated with IgE-DNP and IL33 to assess histamine and IL6 release, respectively. NMSEW mice exhibited increased serum histamine levels (~1.5 fold higher, P&amp;lt;0.05), mesenteric MC numbers (~1.5 fold higher, P=0.05) and MC activation (~2 fold higher, P&amp;lt;0.0001). BMMCs from NMSEW mice exhibited greater histamine content, IgE-mediated histamine release and IL33-stimulated IL6 release (P&amp;lt;0.001), compared with NH BMMCs. Our data demonstrates that ELA induces lasting changes in MC progenitors programming them toward a hyperactive phenotype and increased activation in tissue. Future studies will investigate the mechanisms by which ELA drives lasting hyperactivity of MC progenitors and tissue MC hyperactivity, and its role in MC-related disorders in adulthood.

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin.

Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6weeks. Spleen tyrosine kinase mediates allergen-induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE-mediated histamine release from mast cells in an ex vivo human skin model. Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti-IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC-MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed. Perfused GSK2646264 significantly inhibited anti-IgE (but not C5a)-induced histamine release in a concentration-dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC90 and dose-dependently attenuated anti-IgE-induced histamine release. GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8μM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.

Cell-specific immune-modulation of cadmium on murine macrophages and mast cell lines in vitro.

Toxic trace metals are widespread contaminants that are potentially immunotoxic even at environmentally low exposure levels. They can modulate the immunity to infections, e.g., in wildlife species living in contaminated areas. The diverse immune cell types can be differentially affected by the exposure leading to the modulation of specific protective mechanisms. Macrophages and mast cells, part of the innate immune system, trigger immune responses and perform particular effector functions. The present study compared toxicological and functional effects of cadmium in two models of murine macrophages (RAW264.7 and NR8383 cell lines) and two models of murine mast cells (MC/9 and RBL-2H3 cell lines). Cadmium was selected as a model compound because its known potential to induce reactive oxygen species and its relevance as an environmental contaminant. Mechanisms of toxicity, such as redox imbalance and apoptosis induction were measured in stationary cells, while functional outcome effects were measured in activated cells. Cadmium-depleted glutathione antioxidant in all four cell lines tested although reactive oxygen species was not significantly increased. Mast cells had full dose-response depletion of glutathione below cytotoxic levels while in macrophages the depletion was not complete. Functional endpoints tumour necrosis factor-alpha and nitrite production in lipopolysaccharide-activated macrophages were increased by cadmium exposure. In contrast, mast cell lipopolysaccharide-induced tumour necrosis factor-alpha and IgE-mediated histamine release were reduced by cadmium. These data indicate potentially differential effects of cadmium among murine innate immune cell types, where mast cells would be more susceptible to oxidative stress and their function might be at a higher risk to be modulated compared to macrophages.

The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis.

Systemic mastocytosis is a complex disease defined by abnormal growth and accumulation of neoplastic mast cells in various organs. Most patients exhibit a D816V-mutated variant of KIT, which confers resistance against imatinib. Clinical problems in systemic mastocytosis arise from mediator-related symptoms and/or organ destruction caused by malignant expansion of neoplastic mast cells and/or other myeloid cells in various organ systems. DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis. We found that DCC-2618 inhibits the proliferation and survival of various human mast cell lines (HMC-1, ROSA, MCPV-1) as well as primary neoplastic mast cells obtained from patients with advanced systemic mastocytosis (IC50 <1 μM). Moreover, DCC-2618 decreased growth and survival of primary neoplastic eosinophils obtained from patients with systemic mastocytosis or eosinophilic leukemia, leukemic monocytes obtained from patients with chronic myelomonocytic leukemia with or without concomitant systemic mastocytosis, and blast cells obtained from patients with acute myeloid leukemia. Furthermore, DCC-2618 was found to suppress the proliferation of endothelial cells, suggesting additional drug effects on systemic mastocytosis-related angiogenesis. Finally, DCC-2618 was found to downregulate IgE-mediated histamine release from basophils and tryptase release from mast cells. Together, DCC-2618 inhibits growth, survival and activation of multiple cell types relevant to advanced systemic mastocytosis. Whether DCC-2618 is effective in vivo in patients with advanced systemic mastocytosis is currently under investigation in clinical trials.

Recovery from desensitization of IgE-dependent responses in human lung mast cells.

Clinical desensitization and oral food immunotherapy are therapeutic interventions that allow individuals who react adversely to an allergen (drug or food) to be made tolerant to the allergen. However, tolerance is brief, and allergen hypersensitivity can recur within days following allergen withdrawal. We hypothesize that the reason these treatments are temporary reflects rapid recovery of mast cells from a desensitized state. We sought to test this. Desensitization of IgE-mediated histamine release from human lung mast cells was explored by methods that partially replicate the pattern of treatment during clinical desensitization. Specific and non-specific desensitization and changes in surface IgE were examined following desensitization. Recovery from desensitization was also studied. Desensitization of mast cell responses was readily induced with concentrations of antigen or anti-IgE that were suboptimal for secretion. There was little or no non-specific desensitization when lung mast cells were exposed to antigens. There was no loss of cell surface IgE following desensitization. Removing the desensitizing stimulus from the media following desensitization allowed the cells to recover with half-point of recovery of ~1.5 days and complete recovery after 5 days. Both the functional response and histamine content recovered within this time frame. The recovery appeared possible because both antigens and anti-IgE dissociated rapidly from cells after washing to remove excess stimulus. Human lung mast cells readily recover from a desensitized state following removal of desensitizing antigen. This finding provides a potential explanation for the ephemeral nature of clinical desensitization.

Syk expression and IgE-mediated histamine release in basophils as biomarkers for predicting the clinical efficacy of omalizumab

Syk expression and IgE-mediated histamine release in basophils as biomarkers for predicting the clinical efficacy of omalizumab

Use of Biomarker Based on Human Basophil Syk Expression to Predict the Clinical Efficacy of Omalizumab Treatment in Allergic Asthmatics

Treatment with omalizumab results in the increased sensitivity of basophils to IgE-mediated stimulation, likely due to an increase in syk expression in basophils. Studies in patients with peanut allergy suggested that the increased sensitivity works in opposition to the therapeutic benefits of reduced free IgE. This study examined whether a priori knowledge of syk expression or maximum IgE-mediated histamine release, which is related to syk expression, would provide a predictor of the efficacy of omalizumab in patients with allergic asthma. Adult asthma patients were enrolled and treated with omalizumab for 16 weeks using FDA-approved dosing criteria. Blood basophils were examined for syk expression, IgE-mediated histamine release and changes in these two parameters before and after treatment. Clinical response was measured via a physician’s assessment score (PAS, 1-5 score range, 1 = minimal symptoms) and a final assessment of success. Basophil studies and clinical evaluations were maintained by separate groups. Ten patients satisfied entry criteria (PAS scores of ≥4). For this group, all four metrics, starting syk, changes in syk, starting and changes in histamine release showed a positive chi-square association (p-values ranged 0.0098 to 0.038) with the success of treatment. This study suggests that changes in syk expression and therefore the functionality of human basophils may provide a predictor of successful treatment of asthmatics with omalizumab. Since the change in syk expression is related to starting syk, it is possible that baseline basophil syk or histamine release might be a bio-marker of successful treatment with omalizumab.

A flavanone derivative from the Asian medicinal herb (Perilla frutescens) potently suppresses IgE-mediated immediate hypersensitivity reactions

Perilla frutescens is a dietary leafy herb consumed as a traditional Japanese condiment as well as used for Chinese medicine with anti-inflammatory activity. Here we report a hitherto-unrecognized P. frutescens phytochemical that potently suppresses IgE-mediated type I hypersensitivity reactions. Structural analysis reveals that the purified anti-allergic compound (Perilla-derived methoxyflavanone, PDMF) is identified as 8-hydroxy-5,7-dimethoxyflavanone. PDMF significantly inhibits IgE-mediated histamine release from RBL-2H3 rat basophilic leukemia cells as compared with those seen in known P. frutescens-derived anti-inflammatory polyphenols. We also show that oral administration of PDMF not only suppresses passive cutaneous anaphylaxis, but also prevents allergic rhinitis-like nasal symptoms in a murine model of Japanese cedar pollinosis. Mechanistically, PDMF negatively regulates Akt phosphorylation and intracellular Ca2+ influx, both of which are essential for mast cell secretory granule translocation and its exocytosis upon high-affinity IgE receptor (FcεRI) cross-linking. These results represent PDMF as a new potent anti-allergic phytochemical useful for prevention of IgE-driven hypersensitivity reactions.

Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses.

Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo.

Interval shifts in basophil measures correlate with disease activity in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) significantly impacts the quality of life of those affected through symptoms of pruritus and recurrent skin lesions. In active CSU disease, reduced IgE-mediated basophil histamine release (HR) and basopenia are observed. We sought to examine the relationship between interval changes in basophil measures and shifts in patient-reported disease impairment. Simultaneous symptom and basophil evaluations were completed at two sequential study visits, and interval changes in measures were compared between visits for each subject (n=38). These measures included Skindex-29, current itch and hives scores, total leukocyte histamine content (an indirect measure of blood basophil presence), and basophil HR in response to anti-IgE and formyl-methionine-leucine-phenylalanine. Overall, interval improvements in disease measures in CSU subjects were associated with increased basophil numbers (total leukocyte histamine content) and IgE-mediated HR. This suggests these measures are potential biomarkers for CSU disease improvement and further implicates a role for basophils in CSU.

Basophil Receptor Profiles In Chronic Idiopathic Urticaria

Patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) have a unique basophil phenotype. Reduced IgE-mediated basophil histamine release (HR) and basopenia are observed in active CIU subjects, and these factors are inversely correlated with disease severity. Basophils are recruited from the blood to urticarial lesions in the skin, but the pathways for basophil migration remain unknown. Given the increased levels of chemoattractants in the serum of CIU subjects, we examined the expression of relevant counter receptors on basophils of CIU subjects relative to control groups without skin disease.

Regulation of human skin mast cell histamine release by PDE inhibitors

BackgroundMast cell and basophiles are thought to be central to inflammation that has an allergic basis as allergens activate these cells in an IgE-dependent manner to generate mediators such as histamine, eicosanoids and cytokines. Phosphodiesterase (PDE) is known to exist as multiple molecular forms of enzyme that metabolise the second messengers. Studies of our own have shown that, of a variety of isoform-selective drugs, the PDE4-selective inhibitors, such as rolipram, attenuate the IgE-mediated release of histamine from human basophiles but not from human lung mast cells (HLMC).The main aim of the present study was to characterise the type and role of PDEs regulating human skin mast cells by using selective and non-selective PDE inhibitors. MethodsCells were pre-treated for 15min with these agents and then challenged with an optimal releasing concentration of anti IgE (1:300) for a further 25min for the release of histamine. ResultsThe data show that all the selective PDE-inhibitor compounds (10−5M) were ineffective whereas the non-selective PDE inhibitor, theophylline (10−3M), inhibited histamine release from HSMC (74±4% inhibition; p<0.05). None of the selective PDE inhibitors had any effect on histamine release from HLMC whereas, in basophiles, compounds with activity at PDE 4 (rolipram, denbufylline, Ro-2017, Org 30029) were effective inhibitors of histamine release. ConclusionThe data suggest that unlike most inflammatory cells, PDE-selective inhibitors are ineffective stabilisers of HSMC activity which is similar to HLMC.

Aspirin Augments IgE-Mediated Histamine Release From Human Peripheral Basophils Via Syk Kinase Activation

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exerciseinduced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release. Methods: The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated. Results: Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucylphenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls. Conclusions: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.