scholarly journals Ethanol Extract of Sesamum indicum Linn. Inhibits FcεRI-Mediated Allergic Reaction via Regulation of Lyn/Syk and Fyn Signaling Pathways in Rat Basophilic Leukemic RBL-2H3 Mast Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Hyun Ju Do ◽  
Tae Woo Oh ◽  
Kwang-Il Park
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Inflammatory Mediators ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Sesamum Indicum ◽  
Mast Cell Activation ◽  
Allergic Reactions ◽  
Potent Effect

This study is aimed at determining whether Sesamum indicum Linn. beneficially influences FcεRI-mediated allergic reactions in RBL-2H3 mast cells; it is also aimed at further investigating Lyn/Fyn and Syk signaling pathways. To examine the antiallergic effect of Sesamum indicum Linn. extract (SIE), we treated antigen/immunoglobulin E- (IgE-) sensitized mast cells with extracts of various concentrations. We examined the degranulation release and concentrations of inflammatory mediators. Additionally, the expressions of genes involved in the FcεRI and arachidonate signaling pathways were examined. SIE inhibited the degranulation and secretion of inflammatory mediators in antigen/IgE-sensitized mast cells. SIE reduced the expressions of FcεRI signaling-related genes, such as Syk, Lyn, and Fyn, and the phosphorylation of extracellular signal-regulated kinase in antigen/IgE-sensitized mast cells. Additionally, in late allergic responses, SIE reduced PGD2 release and COX-2 and cPLA2 phosphorylation expression in FcεRI-mediated mast cell activation. Lastly, 250–500 mg/kg SIE significantly attenuated the Ag/IgE-induced passive cutaneous anaphylaxis (PCA) reaction in mice. The potent effect of SIE on RBL-2H3 mast cell activation indicates that the extract could potentially be used as a novel inhibitor against allergic reactions.

scholarly journals Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

2021 ◽  
Vol 12 ◽  
Author(s):  
Lubica Draberova ◽  
Magda Tumova ◽  
Petr Draber
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Inflammatory Mediators ◽  
Pore Formation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Biologically Active ◽  
Mast Cell Activation ◽  
Concentration Changes

Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

scholarly journals The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Maria A. Chelombitko ◽  
Boris V. Chernyak ◽  
Artem V. Fedorov ◽  
Roman A. Zinovkin ◽  
Ehud Razin ◽  
...  
Keyword(s):  
Mast Cell ◽  
Transcription Factors ◽  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Mitochondrial Dynamics ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
Basic Knowledge ◽  
Mitochondrial Activity

Mast cells play a key role in the regulation of innate and adaptive immunity and are involved in pathogenesis of many inflammatory and allergic diseases. The most studied mechanism of mast cell activation is mediated by the interaction of antigens with immunoglobulin E (IgE) and a subsequent binding with the high-affinity receptor Fc epsilon RI (FcεRI). Increasing evidences indicated that mitochondria are actively involved in the FcεRI-dependent activation of this type of cells. Here, we discuss changes in energy metabolism and mitochondrial dynamics during IgE-antigen stimulation of mast cells. We reviewed the recent data with regards to the role played by mitochondrial membrane potential, mitochondrial calcium ions (Ca2+) influx and reactive oxygen species (ROS) in mast cell FcεRI-dependent activation. Additionally, in the present review we have discussed the crucial role played by the pyruvate dehydrogenase (PDH) complex, transcription factors signal transducer and activator of transcription 3 (STAT3) and microphthalmia-associated transcription factor (MITF) in the development and function of mast cells. These two transcription factors besides their nuclear localization were also found to translocate in to the mitochondria and functions as direct modulators of mitochondrial activity. Studying the role played by mast cell mitochondria following their activation is essential for expanding our basic knowledge about mast cell physiological functions and would help to design mitochondria-targeted anti-allergic and anti-inflammatory drugs.

scholarly journals Preventative and Therapeutic Effects of Low-dose Ionizing Radiation on the Allergic Response of Rat Basophilic Leukemia Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hae Mi Joo ◽  
Eun Hee Hong ◽  
Seong-Jun Cho ◽  
Seon Young Nam ◽  
Ji Young Kim
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Ionizing Radiation ◽  
Therapeutic Effect ◽  
Cell Activation ◽  
Low Dose ◽  
Mast Cell Activation ◽  
Allergic Reactions ◽  
Antigen Antibody ◽  
Basophilic Leukemia

Abstract The prevalence of allergies has increased over the last four decades. In allergic reactions, mast cells induce a hypersensitive immune response to a substance that is normally harmless. Ionizing radiation has different biological effects depending on the dose and dose rate. In this study, we investigated whether low-dose irradiation before (preventative effect) or after (therapeutic effect) an antigen-antibody reaction has an anti-allergic effect. To test this, we activated rat basophilic leukemia (RBL-2H3) mast cells with anti-2,4-dinitrophenyl IgE (antibody) and 2,4-dinitrophenyl human serum albumin, which served as an antigen. To test for both the potential of a preventative effect and a therapeutic effect, we irradiated mast cells both before and after mast cell activation, and we measured mediator release and signaling pathway activity. Low-dose ionizing radiation suppressed mediator release from RBL-2H3 mast cells activated by the antigen-antibody reaction regardless of when the mast cells were irradiated. These results were due to the suppression of FcεRI expression. Therefore, we suggest that low-dose ionizing radiation has a preventative and therapeutic effect in allergic reactions via the FcεRI-mediated RBL-2H3 mast cell activation system.

scholarly journals IgE Enhances Mouse Mast Cell FcεRI Expression In Vitro and In Vivo: Evidence for a Novel Amplification Mechanism in IgE-dependent Reactions

1997 ◽  
Vol 185 (4) ◽  
pp. 663-672 ◽  
Author(s):  
Masao Yamaguchi ◽  
Chris S. Lantz ◽  
Hans C. Oettgen ◽  
Ildy M. Katona ◽  
Tony Fleming ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Specific Antigen ◽  
Mast Cell Activation ◽  
Proinflammatory Mediators ◽  
Mouse Mast Cell

The binding of immunoglobulin E (IgE) to high affinity IgE receptors (FcεRI) expressed on the surface of mast cells primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of proinflammatory mediators, which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen-specific mast cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and also contributes to host defense against parasites. We now report that exposure to IgE results in a striking (up to 32-fold) upregulation of surface expression of FcεRI on mouse mast cells in vitro or in vivo. Moreover, baseline levels of FcεRI expression on peritoneal mast cells from genetically IgE-deficient (IgE −/−) mice are dramatically reduced (by ∼83%) compared with those on cells from the corresponding normal mice. In vitro studies indicate that the IgE-dependent upregulation of mouse mast cell FcεRI expression has two components: an early cycloheximide-insensitive phase, followed by a later and more sustained component that is highly sensitive to inhibition by cycloheximide. In turn, IgE-dependent upregulation of FcεRI expression significantly enhances the ability of mouse mast cells to release serotonin, interleukin-6 (IL-6), and IL-4 in response to challenge with IgE and specific antigen. The demonstration that IgE-dependent enhancement of mast cell FcεRI expression permits mast cells to respond to antigen challenge with increased production of proinflammatory and immunoregulatory mediators provides new insights into both the pathogenesis of allergic diseases and the regulation of protective host responses to parasites.

IgE alone-induced actin assembly modifies calcium signaling and degranulation in RBL-2H3 mast cells

2004 ◽  
Vol 286 (2) ◽  
pp. C256-C263 ◽  
Author(s):  
Tatsuya Oka ◽  
Masatoshi Hori ◽  
Akane Tanaka ◽  
Hiroshi Matsuda ◽  
Hideaki Karaki ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
De Novo ◽  
Immunoglobulin E ◽  
Cytochalasin D ◽  
Mast Cell Activation ◽  
Actin Dynamics ◽  
Actin Assembly ◽  
Filamentous Actin

In the mast cell signaling pathways, the binding of immunoglobulin E (IgE) to FcϵRI, its high-affinity receptor, is generally thought to be a passive step. In this study, we examined the effect of IgE alone, that is, without antigen stimulation, on the degranulation in mast cells. Monomeric IgE (500–5,000 ng/ml) alone increased cytosolic Ca2+ level ([Ca2+]i) and induced degranulation in rat basophilic leukemia (RBL)-2H3 mast cells. Monomeric IgE (5,000 ng/ml) alone also increased [Ca2+]i and induced degranulation in bone marrow-derived mast cells. Interestingly, monomeric IgE (5–50 ng/ml) alone, in concentrations too low to induce degranulation, increased filamentous actin content in RBL-2H3 mast cells. We next examined whether actin dynamics affect the IgE alone-induced RBL-2H3 mast cell activation pathways. Cytochalasin D inhibited the ability of IgE alone (50 ng/ml) to induce de novo actin assembly. In cytochalasin D-treated cells, IgE (50 ng/ml) alone increased [Ca2+]i and induced degranulation. We have summarized the current findings into two points. First, IgE alone increases [Ca2+]i and induces degranulation in mast cells. Second, IgE, at concentrations too low to increase either [Ca2+]i or degranulation, significantly induces actin assembly, which serves as a negative feedback control in the mast cell Ca2+ signaling and degranulation.

scholarly journals Tespa1 negatively regulates FcεRI-mediated signaling and the mast cell–mediated allergic response

2014 ◽  
Vol 211 (13) ◽  
pp. 2635-2649 ◽  
Author(s):  
Di Wang ◽  
Mingzhu Zheng ◽  
Yuanjun Qiu ◽  
Chuansheng Guo ◽  
Jian Ji ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
Mast Cell Activation ◽  
Allergic Reactions ◽  
Proinflammatory Cytokine Production ◽  
Increased Sensitivity ◽  
Ige Mediated

Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in their degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. We show that the activation of mast cells is negatively regulated by the newly identified adaptor protein Tespa1. Loss of Tespa1 in mouse mast cells led to hyper-responsiveness to stimulation via FcεRI. Mice lacking Tespa1 also displayed increased sensitivity to IgE-mediated allergic responses. The dysregulated signaling in KO mast cells was associated with increased activation of Grb2-PLC-γ1-SLP-76 signaling within the LAT1 (linker for activation of T cells family, member 1) signalosome versus the LAT2 signalosome. Collectively, these findings show that Tespa1 orchestrates mast cell activation by tuning the balance of LAT1 and LAT2 signalosome assembly.

scholarly journals Recent advances in mast cell activation and regulation

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 196 ◽  
Author(s):  
Hwan Soo Kim ◽  
Yu Kawakami ◽  
Kazumi Kasakura ◽  
Toshiaki Kawakami
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
De Novo ◽  
Immunoglobulin E ◽  
Secretory Granules ◽  
Structural Features ◽  
Mast Cell Activation ◽  
Dependent Manner ◽  
Drug Induced

Mast cells are innate immune cells that intersect with the adaptive immunity and play a crucial role in the initiation of allergic reactions and the host defense against certain parasites and venoms. When activated in an allergen- and immunoglobulin E (IgE)-dependent manner, these cells secrete a large variety of allergenic mediators that are pre-stored in secretory granules or de novo–synthesized. Traditionally, studies have predominantly focused on understanding this mechanism of mast cell activation and regulation. Along this line of study, recent studies have shed light on what structural features are required for allergens and how IgE, particularly anaphylactic IgE, is produced. However, the last few years have seen a flurry of new studies on IgE-independent mast cell activation, particularly via Mrgprb2 (mouse) and MRGPRX2 (human). These studies have greatly advanced our understanding of how mast cells exert non-histaminergic itch, pain, and drug-induced pseudoallergy by interacting with sensory neurons. Recent studies have also characterized mast cell activation and regulation by interleukin-33 (IL-33) and other cytokines and by non-coding RNAs. These newly identified mechanisms for mast cell activation and regulation will further stimulate the allergy/immunology community to develop novel therapeutic strategies for treatment of allergic and non-allergic diseases.

scholarly journals Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor alpha chain respond to human IgE in mast cell degranulation and in allergic reactions.

1996 ◽  
Vol 183 (1) ◽  
pp. 49-56 ◽  
Author(s):  
W P Fung-Leung ◽  
J De Sousa-Hitzler ◽  
A Ishaque ◽  
L Zhou ◽  
J Pang ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Transgenic Mice ◽  
Cell Activation ◽  
Surface Expression ◽  
Mast Cell Activation ◽  
Cell Surface Expression ◽  
Allergic Reactions ◽  
Alpha Chain ◽  
Ige Mediated

The high-affinity receptor for immunoglobulin (Ig) E (Fc epsilon RI) on mast cells and basophils plays a key role in IgE-mediated allergies. Fc epsilon RI is composed of one alpha, one beta, and two gamma chains, which are all required for cell surface expression of Fc epsilon RI, but only the alpha chain is involved in the binding to IgE. Fc epsilon RI-IgE interaction is highly species specific, and rodent Fc epsilon RI does not bind human IgE. To obtain a "humanized" animal model that responds to human IgE in allergic reactions, transgenic mice expressing the human Fc epsilon RI alpha chain were generated. The human Fc epsilon RI alpha chain gene with a 1.3-kb promoter region as a transgene was found to be sufficient for mast cell-specific transcription. Cell surface expression of the human Fc epsilon RI alpha chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in flow cytometric analyses. Expression of the transgenic Fc epsilon RI on bone marrow-derived mast cells was 4.7 x 10(4)/cell, and the human IgE-binding affinity was Kd = 6.4 nM in receptor-binding studies using 125I-IgE. The transgenic human Fc epsilon RI alpha chain was complexed with the mouse beta and gamma chains in immunoprecipitation studies. Cross-linking of the transgenic Fc epsilon RI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the Fc epsilon RI beta and gamma chains and other cellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by beta-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo. The results demonstrate that the human Fc epsilon RI alpha chain alone not only confers the specificity in human IgE binding, but also can reconstitute a functional receptor by coupling with the mouse beta and gamma chains to trigger mast cell activation and degranulation in a whole animal system. These transgenic mice "humanized" in IgE-mediated allergies may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.

scholarly journals Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 251
Author(s):  
Binh Phong ◽  
Lawrence P. Kane
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

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