Role of mast cells in the onset of IgE-mediated late-phase cutaneous response in mice

Nagai, Hiroichi; Abe, Toru; Yamaguchi, Iwao; Mito, Kanako; Tsunematsu, Miwako; Kimata, Masahiro; Inagaki, Nobuya

doi:10.1067/mai.2000.106778

Cited by 20 publications

(14 citation statements)

References 24 publications

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“…The reason for this was probably that the secretion of at least some mast cell-derived mediators essential for the development of the late-phase anaphylaxis reaction, such as IL-6 (ref. 47), was not influenced by Trpm4 deficiency.…”

Section: Discussionmentioning

confidence: 79%

Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4

et al. 2007

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Mast cells are key effector cells in allergic reactions. Aggregation of the receptor FceRI in mast cells triggers the influx of calcium (Ca 2+ ) and the release of inflammatory mediators. Here we show that transient receptor potential TRPM4 proteins acted as calcium-activated nonselective cation channels and critically determined the driving force for Ca 2+ influx in mast cells. Trpm4 -/-bone marrow-derived mast cells had more Ca 2+ entry than did TRPM4 +/+ cells after FceRI stimulation. Consequently, Trpm4 -/-bone marrow-derived mast cells had augmented degranulation and released more histamine, leukotrienes and tumor necrosis factor. Trpm4 -/-mice had a more severe IgE-mediated acute passive cutaneous anaphylactic response, whereas late-phase passive cutaneous anaphylaxis was not affected. Our results establish the physiological function of TRPM4 channels as critical regulators of Ca 2+ entry in mast cells.Mast cells are bone marrow-derived hematopoietic cells localized near surfaces exposed to the environment, such as the skin, the airway epithelia and the intestine, where pathogens, allergens and other environmental agents are frequently encountered 1 . Activation and degranulation of mast cells is a key step in the pathogenesis of allergic diseases such as bronchial asthma and systemic anaphylaxis 2 . An allergic reaction develops when allergens encountered by antigen-presenting cells are processed and presented to T cells. Ensuing T helper type 2 responses cause B cells to produce allergen-specific immunoglobulin E (IgE). The IgE molecules bind to the receptor FceRI on the surfaces of mast cells. After re-exposure to the allergen, FceRI-associated IgE molecules bind allergen and aggregate, thereby activating mast cells. Activated mast cells secrete preformed mediators, including proteases and vasoactive amines, such as histamine, that are stored in cytoplasmic granules. In addition, mast cell activation results in the de novo synthesis of proinflammatory lipid mediators, cytokines and chemokines. The instant release of histamine is crucial for the development of immediate-type allergic reactions that result in vasodilatation, increased vascular permeability and smooth muscle contraction 1,2 . In addition, IgE-dependent mast cell activation may be complemented by signaling cascades triggered by several endogenous ligands, such as adenosine, resulting in the amplification and maintenance of FceRI-mediated degranulation 3,4 .FceRI crosslinking activates many signaling molecules 5,6 . A chief 'downstream' target is phospholipase C-g1, which catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to diacylglycerol and inositol-1,4,5-trisphosphate 5 . In contrast, adenosine stimulation involves the activation of G ai protein-coupled A 3 adenosine receptors in mouse mast cells, which leads to the activation of phospholipase C and phospholipase D through G bg protein and phosphatidylinositol-3-OH kinase-g 7,8 . Inositol-1,4,5-trisphosphate and diacylglycerol promote the activation of protein kinase C an...

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Section: Discussionmentioning

confidence: 79%

Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4

et al. 2007

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“…with 0.5 g anti-DNP IgE. After 24 h a skin reaction was elicited by painting 25 l 0.15% DNFB on both the sides of the ear as has been described previously (31). Ear edema was measured at the times indicated by plythesmometer.…”

Section: Passive Cutaneous Anaphylaxismentioning

confidence: 99%

“…4), which is in accord with our in vitro data showing that STAT6 deficiency does not affect histamine and LTC 4 release from mast cells. We next used a well-characterized mouse model of late phase allergic reactions (31,35), which depends on mast cell-derived TNF-␣ (36). STAT6 ϩ/ϩ and STAT6 Ϫ/Ϫ mice were sensitized i.v.…”

Section: Role Of Stat6 In Ige/fcri Receptor Mediated In Vivo Mast Celmentioning

confidence: 99%

Role of STAT6 in IgE Receptor/FcεRI-Mediated Late Phase Allergic Responses of Mast Cells

Malaviya

Uckun

2002

The Journal of Immunology

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In this study we show that IgE receptor engagement triggers activation of STAT6 in mast cells. We sought to determine the role of STAT6 activation in IgE receptor-mediated mast cell responses using STAT6 knockout mice. After IgE receptor engagement, bone marrow mast cells from STAT6−/− mice exhibited normal histamine and leukotriene C4 release, but their cytokine release was markedly reduced. In accordance with these in vitro data, IgE/Ag-challenged STAT6−/− mice showed normal early phase, but severely impaired late phase, allergic reactions. These findings provide unprecedented evidence that STAT6 plays a pivotal role in mast cell responses to IgE/Ag st imulation.

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“…Activated mast cells play a role in the development of late-phase allergic reactions through the production and release of cytokines (15). To examine the role of MKK3 in late-phase allergic inflammation, MKK3-deficient and wild-type mice were sensitized with anti-DNP IgE i.v.…”

Section: Mkk3 Deficiency Leads To a Deficit In Fc«ri-mediated Latephamentioning

confidence: 99%

MAPK Kinase 3 Specifically Regulates FcεRI-Mediated IL-4 Production by Mast Cells

MacNeil

Yang

Lin

2011

The Journal of Immunology

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Mast cells play a central role in allergic inflammation and are activated through cross-linking of FcεRI receptor-bound IgE, initiating a signaling cascade resulting in production of biologically potent mediators. Signaling pathways in the regulation of specific mediators remain incompletely defined. In this study, we examined the role of MAPK kinase 3 (MKK3) in IgE-dependent mast cell activation. In an in vivo model of passive cutaneous anaphylaxis, MKK3-deficient mice showed a deficit in late-phase IgE-dependent inflammation. To characterize the mechanism of this deficiency, we cultured bone marrow-derived mast cells (BMMCs) from wild-type and MKK3-deficient mice. We found that FcεRI-mediated mast cell activation induced rapid MKK3 phosphorylation by 5 min, diminishing slowly after 6 h. In MKK3-deficient BMMCs, phosphorylation of p38 was reduced at early and later time points. Among 40 cytokines tested using a protein array, IL-4 was the only cytokine specifically downregulated in MKK3-deficient BMMCs. Reduced IL-4 expression was seen in the local skin of MKK3-deficient mice following passive cutaneous allergic reaction. Furthermore, early growth response-1 (Egr1) bound to the promoter of IL-4 in FcεRI-activated mast cells, and Egr1 transcription factor activity was diminished in MKK3-deficient BMMCs. Finally, mast cell-deficient mice reconstituted with MKK3-deficient BMMCs displayed a significantly impaired late-phase allergic inflammatory response. Thus, mast cell MKK3 signaling contributes to IgE-dependent allergic inflammation and is a specific regulator of FcεRI-induced IL-4 production.

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Role of mast cells in the onset of IgE-mediated late-phase cutaneous response in mice

Cited by 20 publications

References 24 publications

Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4

Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4

Role of STAT6 in IgE Receptor/FcεRI-Mediated Late Phase Allergic Responses of Mast Cells

MAPK Kinase 3 Specifically Regulates FcεRI-Mediated IL-4 Production by Mast Cells

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