FcepsilonRI Expression Research Articles

Effect of lipopolysaccharide (LPS) and peptidoglycan (PGN) on human mast cell numbers, cytokine production, and protease composition

BackgroundHuman mast cell (HuMC) maturation occurs in tissues interfacing with the external environment, exposing both mast cell progenitors and mature mast cells, to bacteria and their products. It is unknown, however, whether long- or short-term exposure to bacteria-derived toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS) or peptidoglycan (PGN), influences HuMC biology.ResultsOver 6 wks of culture, LPS had minimal effect on HuMC numbers but increased CD117, tryptase and chymase expression. PGN inhibited HuMC development. For mature mast cells, LPS in the presence of rhSCF (10 ng/ml) increased CD117, tryptase, chymase and carboxypeptidase expression, primarily in CD117low HuMC. LPS decreased FcεRI expression and β-hexosaminidase release; but had no effect on LTC4 and PGD2 production. PGN reduced HuMC numbers; and CD117 and tryptase expression. IL-1β and IL-6 (in addition to IL-8 and IL-12) were detected in short-term culture supernatants of LPS treated cells, and reproduced the increases in CD117, tryptase, chymase, and carboxypeptidase expression observed in the presence of LPS. Comparative studies with mouse bone marrow-derived mast cells from wild type, but not TLR4 knockout mice, showed increases in mRNA of mouse mast cell chymases MMCP-1, MMCP-2 and MMCP-4.ConclusionPGN inhibits HuMC growth, while LPS exerts its primary effects on mature HuMC by altering cytokine production and protease composition, particularly at low concentrations of SCF. These data demonstrate the ability of bacterial products to alter HuMC mediator production, granular content, and number which may be particularly relevant at mucosal sites where HuMC are exposed to these products.

Anti-IgE treatment of eosinophil-associated gastrointestinal disorders

Eosinophil-associated gastrointestinal disorders (EGIDs) are commonly associated with atopy and are being recognized with increasing frequency. Current therapy for EGIDs is inadequate. We sought to determine the efficacy of anti-IgE therapy in EGIDs and investigate the role of IgE in disease pathogenesis. Nine subjects with EGIDs received omalizumab every 2 weeks for 16 weeks while other therapy was held constant. Blood absolute eosinophil counts, tissue eosinophil counts, symptom scores, and free IgE levels were serially measured. Allergen skin testing and flow cytometry for basophil activation and FcepsilonRI were determined at baseline and at week 16. Omalizumab was associated with a decrease in absolute eosinophil count at both the week 16 (34%, P = .004) and combined weeks 12 to 16 (42%, P = .012) time points. Tissue eosinophils decreased in the duodenum (59%) and gastric antrum (69%) but did not reach statistical significance (P = .074 and .098, respectively). Esophageal eosinophil counts remained unchanged. Basophil and dendritic cell FcepsilonRI expression and free IgE levels were all significantly decreased (P < .005). Omalizumab increased the concentration of allergen required to trigger half-maximal basophil activation by 170-fold. Allergen skin test wheal and erythema responses decreased by 78% and 82%, respectively. Symptom scores were decreased at both the midstudy (63%) and end of study (70%) time points (P < .005 for both). These results demonstrate that IgE-mediated processes contribute to the generation of eosinophilic inflammation in EGIDs and suggest that anti-IgE therapy might be effective in these disorders. Anti-IgE might be a potential therapy for EGIDs.

Relationship between the Biological Activities of Methylated Derivatives of (−)-Epigallocatechin-3-O-gallate (EGCG) and Their Cell Surface Binding Activities

It was previously reported that (-)-epigallocatechin-3-O-gallate (EGCG) suppresses the expression of the high-affinity IgE receptor FcepsilonRI in human basophilic cells and that this suppressive effect is associated with EGCG binding to the cell surface. This study examined the effects of five methylated derivatives of EGCG, (-)-epigallocatechin-3-O-(3-O-methyl)gallate (EGCG 3' 'Me), (-)-epigallocatechin-3-O-(4-O-methyl)gallate (EGCG 4' 'Me), (-)-4'-O-methyl-epigallocatechin-3-O-gallate (EGCG 4'Me), (-)-epigallocatechin-3-O-(3,4-O-methyl)gallate (EGCG 3' '4' 'diMe), and (-)-4'-O-methyl-epigallocatechin-3-O-(4-O-methyl)gallate (EGCG 4'4' 'diMe) on FcepsilonRI expression and ERK1/2 phosphorylation, and each of their cell surface binding activities was measured. Of these five methylated derivatives, three that are methylated at the 3' '- and/or 4' '-position, EGCG 3' 'Me, EGCG 4' 'Me, and EGCG 3' '4' 'diMe, suppressed FcepsilonRI expression and ERK1/2 phosphorylation, although the suppressive effects were lower than that of EGCG. EGCG 4'Me and EGCG 4'4' 'diMe, both of which are methylated at the 4'-position, did not demonstrate a suppressive effect. Furthermore, it was found that EGCG 3' 'Me, EGCG 4' 'Me, EGCG 3' '4' 'diMe, and EGCG 4'Me, which are methylated at the 3' '- and/or 4' '-positions or the 4'-position, could bind to the cell surface even though their binding activities were lower than that of EGCG. Only EGCG 4'4' 'diMe, which is methylated at both the 4'- and 4' '-positions, could not bind. These results suggest that the trihydroxyl structure of the B ring is essential for EGCG to exert the suppressive effects and that the hydroxyl groups on both the 4'-position in the B ring and the 4' '-position in the gallate are crucial for the cell surface binding activity of EGCG.

Dietary flavones suppresses IgE and Th2 cytokines in OVA-immunized BALB/c mice

The flavonoids are a diverse family of chemicals commonly found in fruits and vegetables. Previously, we have shown that the two flavones, chrysin and apigenin could suppress the expression of the high affinity IgE receptor FcepsilonRI in human basophilic KU812 cells. We also demonstrated that dietary apigenin decreased IgE level in C57BL/6N mice sera. To evaluate the anti-allergic effect of the two flavones in vivo, we evaluated the effect of the two flavones, chrysin and apigenin, on the immune system in BALB/c mice sensitized with ovalbumin (OVA). Mice were fed experimental diets containing either of the flavones for 3 weeks and immunized with OVA. After the experimental feeding period, measurement of Igs concentration in the mice sera was performed using a sandwich ELISA. Cytokines expression in mice sera was assessed using a cytokine array. Furthermore, cytokines mRNA levels in spleen lymphocytes from mice sensitized with OVA were measured by RT-PCR. The total IgE level in mice fed one of the two flavones were suppressed, whereas levels of IgG, IgM, and IgA were not affected. The production of interleukin (IL)-4, which is known as one of Th2 cytokines and regulates the production of IgE, was down-regulated by the chrysin or the apigenin diet. Moreover, OVA-induced mRNA expression of Th2 cytokines in spleen lymphocytes from mice sensitized with OVA, such as IL-4 and IL-13 were down-regulated by the chrysin or the apigenin diet. The results suggest that the diet containing one of the two flavones might suppress the up-regulation of serum IgE induced by OVA-immunization through the suppression of Th2-type immune response.

Generation of a Considerable Number of Functional Mast Cells with a High Basal Level of FcɛRI Expression from Cord Blood CD34+Cells by Co‐culturing Them with Bone Marrow Stromal Cell Line Under Serum‐free Conditions

The number of mast cells (MC) that can be obtained from tissue is limited, making it difficult to study the role of MC. Cultured MC derived from cord blood (CB)-CD34(+) cells proliferate well compared with those derived from adult CD34(+) cells; however, they have been reported to be phenotypically or functionally immature regardless of culture system. For example, very few cells express FcepsilonRI. To resolve this problem, we addressed the effect of human bone marrow stromal cell line on the development of cultured MC. CB-CD34(+) (1 x 10(4)) cells were cultured for 8 weeks in a serum-free medium containing rhIL-6 and rhSCF with or without a human bone marrow stromal cell line, namely, co-culture and liquid culture, and were compared in various regards. MC were basically determined by metachromatic staining of granules. The number of MC obtained (60.3 +/- 15.8 x 10(5) versus 2.0 +/- 1.0 x 10(5)), percentage of FcepsilonRI(+) cells (29.3 +/- 9.4% versus 1.9 +/- 0.8%), histamine content (9.7 +/- 2.8 pg/cell versus 5.8 +/- 2.3 pg/cell), and IgE-mediated histamine release (46 +/- 10% versus 17 +/- 7%) were higher (P < 0.01 and P < 0.05) in the co-culture than in the liquid culture. When CB-CD34(+) cells were developed in liquid culture with the co-culture supernatant (CM), a significant increase (P < 0.01) in the percentage of FcepsilonRI(+) cells and in cell number was observed but these values were lower than those of co-cultured MC. We concluded that this co-culture system was useful for obtaining a considerable number of mature MC with a high basal level of functional FcepsilonRI expression from CB-CD34(+) cells. Yet unknown humoral factors in CM may partly mediate this effect.

Decoding IgE Fc receptors

Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic diseases by interacting with two membrane receptors: high-affinity FcepsilonRI and low-affinity FcepsilonRII (CD23). Allergeninduced IgE-occupied FcepsilonRI aggregation on the mast cell or basophil cell surface leads to the activation of intracellular signaling events and eventually the release of pre-formed and de novo synthesized inflammatory mediators. The role of FcepsilonRII in allergic diseases has been proposed to include regulation of IgE synthesis, enhanced histamine release from basophils, and a contribution to Ag-IgE complex presentation but the exact function of CD23 remains poorly understood. This review summarizes some new developments in IgE Fc-receptor studies with an emphasis on regulation of FcepsilonRI expression and signal transduction, including monomeric IgE, lipid raft segregation, and some recently identified negative regulators. A better understanding of signaling events following IgE FcR aggregation will shed new light on how allergy patients might be treated more safely and effectively.

Relationship between spleen tyrosine kinase and phosphatidylinositol 5′ phosphatase expression and secretion from human basophils in the general population

Previous studies have suggested that expression levels of spleen tyrosine kinase (syk) or phosphatidylinositol 5' phosphatase (SHIP) may explain certain extreme human basophil phenotypes. This study is designed to explore whether variability in syk and SHIP expression levels in the general population, alone or in concert, can account for the variability in basophil function. A survey of maximum responsiveness to IgE-mediated stimulation, sensitivity, and expression levels of 6 early signaling elements was performed on 36 subjects' basophils. Of the 6 signaling elements, only syk and SHIP showed a correlation with maximum histamine release or cellular sensitivity. In a multiple regression, syk and SHIP together could account for 67% of population variance, although most of the variance was explained by syk expression. The pattern of expression variance syk>>SHIP1>SHIP2 approximately lyn approximately p85 approximately cbl suggested a process that primarily modulated syk levels. IL-3 is known to modulate syk levels, but we found that a 3-day incubation with IL-3 resulted in increased expression of other signaling elements to a greater degree: cbl>SHIP1>SHIP2 approximately lyn approximately p85 > or = syk, opposite the pattern in the population survey. In contrast, 18-hour stimulation with anti-IgE antibody led to marked downregulation of syk expression, modest downregulation of Fc epsilon RI expression, weak downregulation of lyn expression, and no effect on 23 other signaling elements. Unlike studies in mice, we conclude that expression of syk is a good preconditioning predictor of basophil function in the general population. The finding that expression of syk levels may strongly influence functional responses of basophils suggests a mechanism underlying the severity of atopic diseases.

Lipoteichoic Acid and Peptidoglycan Inhibit Fc Epsilon RI Expression by Mast Cells

Lipoteichoic Acid and Peptidoglycan Inhibit Fc Epsilon RI Expression by Mast Cells

Comparative analysis of nasal and oral mucosa dendritic cells

Mucosal dendritic cells (DC) play a crucial role in tolerance induction as seen in mucosal immunotherapy of atopic diseases. Nevertheless little is known about the phenotypical differences of oral and nasal mucosal DC (nmDC). Recently, we could show that oral mucosal myeloid CD1a(+) DC (omDC) differ from their skin counterparts especially by the expression of high affinity receptor for immunoglobulin E (IgE; FcepsilonRI). However, expression pattern of FcepsilonRI and phenotypical characteristics of CD1a(+) nmDC have not been elucidated in detailed yet. We performed detailed phenotypical comparison of nmDC and omDC of atopic and nonatopic individuals. As reported for omDC, FcepsilonRI on nmDC of atopic donors was elevated and mostly occupied by IgE while FcepsilonRI was present only in low amounts on nmDC of nonatopic donors. Nevertheless, the highest FcepsilonRI expression has been observed on omDC. Furthermore, significant amounts of costimulatory molecules CD40, CD80 and CD86 could be detected on nmDC that expressed more CD80 compared with omDC. Moreover, nmDC displayed less major histocompatability complex (MHC) class I and II molecules than omDC. In addition, nmDC expressed more C-type lectins CD205, CD206 as well as myeloid marker CD11b while omDC displayed increased expression of CD207 and lipopolysaccharide (LPS) receptor CD14. Together these data imply that nmDC phenotypical differ from omDC which might result in diverse functional properties and might be of relevance for selecting routes for immunotherapy of atopic diseases. Moreover these data provide a basis for further studies investigating immunological mechanisms underlying mucosal immunotherapy.

GATA-1 is required for expression of FcεRI on mast cells: analysis of mast cells derived from GATA-1 knockdown mouse bone marrow

The high-affinity receptor for IgE (FcepsilonRI) that is expressed on the surface of mast cells plays an important role in antigen/IgE-mediated allergic reactions. We have previously found that critical elements in the promoter of the FcepsilonRI alpha- and beta-chain genes are recognized by the transcription factor GATA-1 in electrophoretic mobility shift assays coupled with a transient expression system for the alpha- and beta-chain promoters. To confirm that GATA-1 is involved in the expression of FcepsilonRI definitively, we generated bone marrow-derived mast cells from GATA-1 knockdown (KD) heterozygous mice. FACS analysis showed that the frequency of FcepsilonRI-positive cells was significantly decreased in mast cells derived from bone marrow of GATA-1 KD mice. Reverse transcription-PCR analysis showed that the level of transcripts not only for GATA-1 but also for both the alpha- and beta-chains was significantly lower in KD mast cells, whereas that of the FcepsilonRI gamma-chain was not affected. Degranulation caused by cross-linking of FcepsilonRI on mast cells prepared from KD mice was markedly repressed in comparison with that of wild-type mast cells. We concluded that the transcription factor GATA-1 positively regulates FcepsilonRI alpha- and beta-chain expression and therefore is involved in mast cell development.

The Immunoglobulin E receptor: Expression and regulation

The interaction of immunoglobulin E (IgE) and its receptors is critical for the manifestation of allergic disease. Currently, IgE receptors include the high-affinity Fc epsilonRI and the low-affinity Fc epsilonRII. Fc epsilonRI is a tetrameric or trimeric complex, and each has distinct expression patterns and unique functional consequences. In general, serum levels of IgE regulate Fc epsilonRI expression, and novel therapies that lower the concentration of IgE have provided insights into the contribution of this receptor in allergic disease. Newer therapies targeting Fc epsilonRI-signaling elements and the low-affinity IgE receptor, Fc epsilonRII (CD23), are being developed.

Flavones Suppress the Expression of the High-Affinity IgE Receptor FcεRI in Human Basophilic KU812 Cells

We examined the effect of flavones on the expression of the high-affinity IgE receptor FcepsilonRI, which plays a central role in the IgE-mediated allergic response. Flow cytometric analysis showed that the flavones chrysin and apigenin were able to reduce the cell surface expression of FcepsilonRI in human basophilic KU812 cells. Immunoblot analysis revealed that the total cellular expression of the FcepsilonRI alpha and gamma chains decreased upon treatment with chrysin and apigenin. Moreover, the level of mRNA expression of the FcepsilonRI alpha and gamma chains also decreased when the cells were cultured with the two flavones. Previously, we demonstrated that the reduction of extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation was involved in the downregulation of FcepsilonRI expression. The two flavones were shown to reduce the level of ERK1/2 phosphorylation. These results suggested that chrysin and apigenin have the ability to downregulate FcepsilonRI expression and this suppressive effect may be due to the reduction of ERK1/2 phosphorylation.

Omalizumab in Asthma: Approval and Postapproval Experience

Omalizumab is a humanized mouse monoclonal antibody that binds specifically to the constant region of the immunoglobulin (Ig)E heavy chain. Omalizumab exerts its effects by reducing free serum IgE levels and FcepsilonRI expression on several cell types. These effects have been shown to result in decreased airway inflammation and clinical improvement. In multiple studies, omalizumab has been shown to be efficacious in the treatment of moderate-to-severe persistent asthma and is currently approved by the US Food and Drug Administration for the treatment of moderate-to-severe allergic asthma in patients age 12 yr and older. Moreover, omalizumab has been demonstrated to be effective in the treatment of children and adults with seasonal and perennial allergic rhinitis. Postmarketing surveillance has shown omalizumab to be a relatively safe and well-tolerated medication.

Calcium Response and Fc.EPSILON.RI Expression in Bone Marrow-Derived Mast Cells Co-cultured with SCG Neurites

Communication between nerves and mast cells is a prototypic demonstration of neuro-immune interaction. Numerous studies have shown that the stimulation of nerves (or addition of neurotransmitters) can evoke activation of mast cells, and that mast cell-derived mediators can influence neuronal activity. However, it is still unknown whether high affinity IgE receptors (FcepsilonRI) themselves are involved directly in the communication between nerves and mast cells. In the present experiments, we used an in vitro co-culture approach comprising interaction between immune (bone marrow-derived mast cells, BMMCs) and nerve cells (superior cervical ganglia, SCG) to solve the above problem. We found that the intracellular calcium ion concentration ([Ca2+]i) increased much more in BMMCs after antigen (DNP7-BSA) stimulation when they were associated with SCG neurites in the co-culture system. But the [Ca2+]i in BMMCs was less increased when they were not associated with the neurites. Further, the in vitro co-culture approach of BMMCs with SCG neurites for 3 d showed the increases of FcepsilonRI expression occurred on the plasma membranes of BMMCs which were attached to the neurites. On the contrary, N-cadherin molecules which localized on the interface between on the plasma membrane of BMMCs and SCG neurites did not increase with the co-culture for 3 d. All of these results indicated that co-culturing BMMCs with SCG neurites for 3 d promoted not only the calcium response but also the FcepsilonRI expression in BMMCs.

Anti-IgE therapy.

IgE has a central role in the initiation of allergic hypersensitivity reactions. Pioneered by the development of humanized monoclonal antibodies directed against IgE, anti-IgE therapy represents an original approach to the treatment of allergic disease and has demonstrated promise in preventing the symptoms of asthma, allergic rhinitis, and food allergy. The primary mechanism of action of anti-IgE therapy is the reduction in serum levels of IgE and FcepsilonRI expression on mast cells and basophils.

Transforming Growth Factor-β1 Regulates the Expression of the High-Affinity Receptor for IgE on CD34+ Stem Cell-Derived CD1a+ Dendritic Cells In Vitro

It has been reported that monocytes, Langerhans cells (LC) and other dendritic cells (DC) express the high-affinity receptor for IgE (FcepsilonRI) in patients with atopic diseases. These cells may be instrumental in the control of the immune response and the allergic inflammation. In this context, transforming growth factor beta 1 (TGF-beta1) has been highlighted as a key cytokine involved in the mechanisms aimed to orchestrate tolerance and has been suggested as a candidate gene in atopic diseases. In this report, we investigate the putative role of TGF-beta1 in the regulation of FcepsilonRI on cord blood CD34+ stem cell-derived CD1a+ DC (CD34-derived CD1a+ DC). Kinetic experiments show that FcepsilonRI spontaneously appears on the surface of CD1a+ DC, but decreases when exogenous TGF-beta1 is added at high doses (10 ng per mL) or when endogenous TGF-beta1 is neutralized in the culture conditions. In contrast, low-dose TGF-beta1 (0.5 ng per mL) stabilizes surface FcepsilonRI expression on DC. Increasing TGF-beta1 concentrations leads to the generation of LC-like DC showing an augmentation in stimulatory capacity towards allogeneic T cells. In view of these data, a picture emerges that FcepsilonRI+ on DC is finely modified by the TGF-beta1 concentration in the microenvironment and could be of primary relevance in the context of atopic diseases.

Early divergence of Fc epsilon receptor I signals for receptor up-regulation and internalization from degranulation, cytokine production, and survival.

Mast cells play a critical role in IgE-dependent immediate hypersensitivity. Monomeric IgE binding to its high affinity receptor (FcepsilonRI) results in a number of biological outcomes in mouse mast cells, including increased surface expression of FcepsilonRI and enhanced survival. IgE molecules display heterogeneity in inducing cytokine production; highly cytokinergic IgEs cause extensive FcepsilonRI aggregation, leading to potent enhancement of survival and other activation events, whereas poorly cytokinergic IgEs can do so less efficiently. In this study, we demonstrate that IgE-induced receptor up-regulation is not sensitive to monovalent hapten, which can prevent receptor aggregation induced by IgE, whereas other activation events such as receptor internalization, degranulation, IL-6 production, and survival are sensitive to monovalent hapten. IgE-induced receptor up-regulation is also unique in that no Src family kinases, Syk, or Btk are required for it. By contrast, highly cytokinergic IgE-induced receptor internalization is dependent on Lyn, but not other Src family kinases, Syk, or Btk, whereas degranulation, IL-6 production, and survival require Syk. Weak to moderate stimulation with IgE plus anti-IgE or IgE plus Ag enhances survival, while stronger signals are required for degranulation and IL-6 production. Collectively, signals emanated from IgE-bound FcepsilonRI for receptor up-regulation and internalization are shown to diverge at the receptor or receptor-proximal levels from those for other biological outcomes.

Comparative immunophenotyping of monocytes from symptomatic and asymptomatic atopic individuals

Allergy has at least two components - a genetic predisposition referred to as atopy and the progress from an atopic state to clinically apparent disease. Peripheral blood monocytes are circulating myeloid precursors of antigen-presenting cells. The expression of cell surface proteins on monocytes may therefore witness the disease status and affect the development of allergic disease. Monocytes were isolated from atopic individuals with seasonal allergic rhinitis (n = 10), from atopic individuals sensitized to aeroallergens but without any signs of acute disease (n = 11), and from healthy nonatopic donors (n = 21). Detailed comparative phenotypic analysis of CD14(+) and FcepsilonRI(+)CD14(+) monocytes was performed by flow cytometry. CD14(+) monocytes from symptomatic atopic donors showed a significant increase in the cell surface intensity of the integrin adhesion molecule CD11c over monocytes from asymptomatic atopic and nonatopic donors. Asymptomatic atopic individuals showed significantly enhanced expression of FcepsilonRI on the CD14(high)CD16(dim) monocyte subset compared with this subset from symptomatic atopic and nonatopic donors. The increase in monocyte surface intensity of the adhesion molecule CD11c may be involved in the manifestation of allergic disease. FcepsilonRI on CD14(high)CD16(dim) monocytes of asymptomatic atopic donors may be of functional importance for the maintenance of clinical unresponsiveness toward allergens.

P28, a Novel IgE Receptor-associated Protein, Is a Sensor of Receptor Occupation by Its Ligand in Mast Cells

Mast cells express the high affinity receptor for IgE (FcepsilonRI). Aggregation of this receptor by IgE and antigen leads to a signaling cascade resulting in the secretion of histamine, in the synthesis of other pro-inflammatory mediators such as leukotrienes and prostaglandins, and in the production of various cytokines, all of which participate in the development of the allergic reaction. In the last years, growing evidence accumulated that binding of IgEs to FcepsilonRI in itself induces active signals leading to mast cell survival, increased expression of FcepsilonRI, transient induction of histidine decarboxylase synthesis, and increased cell adhesion. The mechanisms underlying monomeric IgE signaling in the absence of receptor aggregation are still poorly understood. Here, we show that a protein of 28 kDa (p28) is physically and constitutively associated with FcepsilonRI in mast cells. Coimmunoprecipitation studies from (125)I surface-labeled cells demonstrated that this association involves at least 50% of membrane-expressed FcepsilonRI. After the addition of monomeric IgE to the cells, the p28.FcepsilonRI complex dissociates almost completely in less than 2 min. This dissociation is temperature-sensitive and is not due to the recruitment of additional proteins to the complex. Stripping bound IgE from the cells by acidic treatment promotes a rapid reassociation between p28 and FcepsilonRI. Altogether, these data are consistent with a conformational regulation of the complex. Thus, p28 is a sensor for FcepsilonRI occupation by IgE on mast cells, and its dissociation from the receptor could represent an early step of monomeric IgE signaling.

IL-10 inhibits Fc epsilon RI expression in mouse mast cells.

FcepsilonRI expression and function is a central aspect of allergic disease. Using bone marrow-derived mouse mast cell populations, we have previously shown that the Th2 cytokine IL-4 inhibits FcepsilonRI expression and function. In the current study we show that the Th2 cytokine IL-10 has similar regulatory properties, and that it augments the inhibitory effects of IL-4. FcepsilonRI down-regulation was functionally significant, as it diminished inflammatory cytokine production and IgE-mediated FcepsilonRI up-regulation. IL-10 and IL-4 reduced FcepsilonRI beta protein expression without altering the alpha or gamma subunits. The ability of IL-4 and IL-10 to alter FcepsilonRI expression by targeting the beta-chain, a critical receptor subunit known to modulate receptor expression and signaling, suggests the presence of a Th2 cytokine-mediated homeostatic network that could serve to both initiate and limit mast cell effector function.