TY - JOUR. T1 - Involvement of p38 MAP kinase and Smad3 in TGF-β-mediated mast cell functions. AU - Funaba, Masayuki. AU - Ikeda, Teruo. AU - Murakami, Masaru. AU - Ogawa, Kenji. AU - Nishino, Yoshii. AU - Tsuchida, Kunihiro. AU - Sugino, Hiromu. AU - Abe, Matanobu. PY - 2006/12/1. Y1 - 2006/12/1. N2 - Transforming growth factor-β (TGF-β) modulates functions of bone marrow-derived cultured mast cells (BMMCs); cell maturation (up-regulation of mouse mast cell proteases (mmcps)), growth arrest and migration. We investigated the roles of p38 MAP kinase and Smad3 in TGF-β-mediated cell responses in BMMCs. Treating BMMCs with TGF-β induced the phosphorylation of p38 within 2 h and persisted for 24 h. The involvement of p38 in TGF-β-induced cell responses depended upon mast cell functions; it was necessary for up-regulation of mmcp-1 and migration, but not for up-regulation of mmcp-7 and inhibition of metabolic activity. New protein synthesis was required for the up-regulation of mmcp-1 but not ...
TY - JOUR. T1 - Proliferative quiescence of normal mast cells resembles that of cold-sensitive mutant mastocytoma cells. Dominant expression of the quiescent state in heterokaryons. AU - Laeng, H.. AU - Harris, David T.. AU - Schindler, R.. PY - 1985. Y1 - 1985. N2 - Normal murine peritoneal mast cells were fused to serum-deprived, non-proliferating cells of a cultured subline (41-SB-4) of the P-815 murine mastocytoma. Upon reincubation in medium containing 10% horse serum for 48 h, mono- and binuclear 41-SB-4 cells reentered S phase of the cell cycle, while mast cell × 41-SB-4 heterokaryons as well as mono- and binuclear mast cells remained in proliferative quiescence, indicating dominant expression of the quiescent state of mast cells. The quiescent state of normal mast cells thus resembles that of cold-sensitive (cs) mutant cells (21-F) of the undifferentiated P-815 mastocytoma: at the non-permissive temperature of 33 °C, the 21-F cells were found to enter a state of quiescence which is ...
Background: Mast cells infiltrate the bronchial smooth muscle (BSM) in asthmatic patients, but the mechanism of mast cell adhesion is still unknown. The adhesion molecules CD44 (i.e. hyaluronate receptor) and CD51 (i.e. vitronectin receptor) are widely expressed and bind to many extracellular matrix (ECM) proteins. The aims of the study are (i) to identify the role of ECM in mast cell adhesion to BSM and (ii) to examine the role of CD51 and CD44 in this adhesion.. Methods: Human lung mast cells, human mast cell line (HMC-1), and BSM cells from control donors or asthmatic patients were cultured in the presence/absence of various cytokines. Mast cell-BSM interaction was assessed using 3H-thymidine-pulsed mast cells, confocal immunofluorescence, or electron microscopy. Adhesion molecules expression and collagen production on both cell types were evaluated by quantitative RT-PCR, western blot, and flow cytometry.. Results: Mast cell adhesion to BSM cells mostly involved type I collagen of the ECM. ...
BACKGROUND: In asthma and other allergic disorders, the activation of mast cells by IgE and antigen induces the cells to release histamine and other mediators of inflammation, as well as to produce certain cytokines and chemokines. To search for new mast cell products, we used complementary DNA microarrays to analyze gene expression in human umbilical cord blood-derived mast cells stimulated via the high-affinity IgE receptor (Fc(epsilon)RI).. RESULTS: One to two hours after Fc(epsilon)RI-dependent stimulation, more than 2,400 genes (about half of which are of unknown function) exhibited 2-200 fold changes in expression. The transcriptional program included changes in the expression of IL-11 and at least 30 other cytokines and chemokines. Human mast cells secreted 130-529 pg of IL-11/106 cells by 6 h after stimulation with anti-IgE.. CONCLUSION: Our initial analysis of the transcriptional program induced in in vitro-derived human mast cells stimulated via the Fc(epsilon)RI has identified many ...
Mast cell activation causes degranulation and release of cytokines, thereby promoting inflammation. The aim of this study was to investigate the inhibitory effect of CDK4/6 inhibition on mast cell activation in vitro and in vivo. RBL-2H3 rat basophilic leukemia cells (BLCs) and mouse bone marrow-derived mast cells (BMMCs) were sensitized with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated with DNP-human serum albumin (HSA) antigens, and treated with the CDK4/6 inhibitor palbociclib. Histological stains were applied to reveal cytomorphological changes. Murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models were used to examine palbociclib effects on allergic reactions in vivo. Western blots were performed to detect the expression of cell signaling molecules associated with mast cell activation. Activated BLCs and BMMCs released copious granule-related mediators (histamine and β-hexosaminidase), which was reduced
Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and ...
Intravital multiphoton microscopy has provided insightful information of the dynamic process of immune cells in vivo. However, the use of exogenous labeling agents limits its applications. There is no method to perform functional imaging of mast cells, a population of innate tissue-resident immune cells. Mast cells are widely recognized as the effector cells in allergy. Recently their roles as immunoregulatory cells in certain innate and adaptive immune responses are being actively investigated. Here we report in vivo mouse skin mast cells imaging with two-photon microscopy using endogenous tryptophan as the fluorophore. We studied the following processes. 1) Mast cells degranulation, the first step in the mast cell activation process in which the granules are released into peripheral tissue to trigger downstream reactions. 2) Mast cell reconstitution, a procedure commonly used to study mast cells functioning by comparing the data from wild type mice, mast cell-deficient mice, and mast-cell deficient
c-kit ligand (KL) activated mouse bone marrow-derived mast cells (BMMC) for the dose- and time-dependent release of arachidonic acid from cell membrane phospholipids, with generation of leukotriene (LT) C4 in preference to prostaglandin (PG)D2. KL at concentrations of 10 ng/ml elicited half-maximal eicosanoid generation and at concentrations of , 50 ng/ml elicited a maximal generation of approximately 15 ng LTC4 and 1 ng PGD2 per 10(6) cells, with 20% net beta-hexosaminidase release 10 min after stimulation. Of the other cytokines tested, none, either alone or in combination with KL, elicited or modulated the immediate phase of mediator release by BMMC, indicating strict specificity for KL. Activation of BMMC in response to KL was accompanied by transient phosphorylation of cytosolic phospholipase A2 and reversible translocation of 5-lipoxygenase to a cell membrane fraction 2-5 min after stimulation, when the rate of arachidonic acid release and LTC4 production were maximal. BMMC continuously ...
Resveratrol, a polyphenol abundant in peanuts, red wine and the skin of grapes, has been shown to have anti-cancer, anti-oxidant and anti-inflammatory activities, and may also have beneficial effects on allergic inflammation. We investigated the effects of resveratrol on human mast cell activation in comparison to the anti-allergy drug tranilast. In LAD2 mast cells, both resveratrol and tranilast inhibited degranulation induced by the mast cell activators substance P, IgE/anti-IgE, and compound 48/80. Resveratrol inhibition was immediate, preventing degranulation when added simultaneously to physiological stimuli, and the effect was sustained for up to 24 hrs. The inhibitory effect was not cAMP dependent, but may be attributable to calcium modulation, as resveratrol, and to a lesser extent tranilast, prevented substance P-induced increases in intracellular calcium. Resveratrol attenuated substance P-induced TNF and MCP-1 production and inhibited IgE-mediated release of cysteinyl leukotrienes, whereas
TY - JOUR. T1 - Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells. AU - Sawamukai, Norifumi. AU - Saito, Kazuyoshi. AU - Yamaoka, Kunihiro. AU - Nakayamada, Shingo. AU - Ra, Chisei. AU - Tanaka, Yoshiya. PY - 2007/11/15. Y1 - 2007/11/15. N2 - Mast cells release many inflammatory mediators that play an important role not only in allergic diseases but also in chronic inflammatory diseases, autoimmune diseases, and others. A lot of mast cells exist in synovium of rheumatoid arthritis, and it is known that synovitis does not occur in mast cell-deficient mice. Thus, it is thought that mast cells play a very important role in rheumatoid arthritis pathogenesis. Leflunomide is a drug used clinically in the treatment of rheumatoid arthritis. We used clinical doses of 2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-butenamide (A77 1726), which is an active metabolite of leflunomide, and decreased the number of viable human primary mast cells in a concentration-dependent manner. ...
Exposure to monomeric IgE in vitro markedly upregulated the ability of mature mouse peritoneal mast cells or mouse BMCMCs or cloned mast cells to bind IgE. Two separate lines of evidence indicate that this response largely, if not entirely, reflected the increased surface expression of FcεRI. First, while mouse mast cells also express FcγRII/ III ((17), (18)), which can bind IgE immune complexes ((18)), virtually all of the binding of monomeric IgE to mouse mast cells that is detectable under the conditions used in our experiments reflects binding of the ligand to a single class of high affinity binding sites, i.e., FcεRI ((18)). Second, we used anti-IgE to immunoprecipitate surface-bound IgE, and associated IgE receptors, from lysates of BMCMCs that had been first incubated with or without IgE at 5 μg/ml for 21 h and then exposed briefly to excess IgE just before recovery for flow cytometry and Western blot analysis. We found that, in comparison to aliquots of the same mast cell population ...
TY - JOUR. T1 - Progress in allergy signal research on mast cells. T2 - Signal regulation of multiple mast cell responses through FcεRI. AU - Yamasaki, Shou. AU - Saito, Takashi. PY - 2008/4/8. Y1 - 2008/4/8. N2 - The crosslinking of FcεRI by IgE and antigen (Ag) on mast cells initiates activation cascades that lead to allergic responses. Although it was thought that IgE binding to FcεRI is a passive "sensitization", recent reports suggest that IgE actively promotes mast cell survival in the absence of Ag. However, it is largely unknown how these distinct responses are delivered through the same receptor, FcεRI, depending on the types of stimli. As an underlying molecular mechanism for the generation of diverse responses through FcεRI, we found that the quantity and the duration of the signal through the FcεRI γ chain (FcRγ) determine different mast cell responses. Furthermore, FcRγ-mediated sustained Erk activation is critical for IgE-induced mast cell survival through autocrine ...
In this study the diversity of mast cell proteases and some of the factors regulating mast cell growth and protease expression were examined in rodents. Five proteases were isolated from mouse small intestinal mucosa and their substrate specificities defined. The isolated proteases were all of mast cell origin and were chymotrypsin-like in their substrate specificities. The proteases were all identified as variants of mouse mast cell protease-1 which differed only in their carbohydrate moieties. Despite the fact that these enzymes shared a common core polypeptide they all differed significantly in the rate at which they hydrolysed synthetic substrates and in the rates at which they were inhibited by α1-proteinase inhibitor. A related, but distinct protease was isolated from peritoneal cavity mast cells of mice. This enzyme, also a chymase, had N-terminal sequence identity with mouse mast cell protease-4. This enzyme was not inhibited by α1-proteinase inhibitor. Factors which regulate mast cell ...
Mast cells are best known for their function in hypersensitive reactions, where aggregation of FcRI leads to the release of mast cell mediators leading to hypersensitive symptoms. although activation-induced success is certainly suffered, suggesting a minimal function for Bcl-XL, Bcl-2, Mcl-1 and Bcl-w. Reducing but not really amounts by siRNA inhibited activation-induced mast cell success. We also demonstrate that mast cell phrase of Bfl-1 is certainly raised in birch-pollen-provocated epidermis and in lesions of atopic dermatitis and psoriasis sufferers. Used jointly, our outcomes high light Bfl-1 as a main effector in activation-induced individual mast cell success. Launch Mast cells are known to end up being central regulators and effectors in allergic illnesses. When a multivalent antigen binds to IgE occupying the high affinity receptor for IgE (FcRI), receptor aggregation and following mast cell account activation takes place. This total result in mast cell degranulation, adjustments in ...
The mechanism of chronic mast cell activation in asthma is unclear. Monomeric immunoglobulin (Ig)E in the absence of allergen induces mediator release from rodent mast cells, indicating a possible role for IgE in the continued activation of mast cells within the asthmatic bronchial mucosa. In this study it was investigated whether monomeric IgE induces Ca2+ influx and mediator release from human lung mast cells (HLMC). Purified HLMC were cultured for 4 weeks and then exposed to monomeric human myeloma IgE. Ratiometric Ca2+ imaging was performed on single fura-2-loaded cells. Histamine release was measured by radioenzymatic assay; leukotriene C4 (LTC4) and interleukin (IL)-8 were measured by ELISA. At concentrations experienced in vivo, monomeric IgE induced dose-dependent histamine release, LTC4 production and IL-8 synthesis. This was associated with a rise in cytosolic free Ca2+. Enhanced histamine release was still evident 1 week after initial exposure to IgE suggesting that continued exposure ...
Previous in vitro studies have shown biphasic effects of adenosine on mast cell activity; however, the receptor subtypes that mediate the inhibitory effects of adenosine are still controversial (Peachell et al., 1991; Yip et al., 2009). Mast cells express two distinct Gs-coupled adenosine receptors; their biologic roles have not been comprehensively defined, especially in vivo. Since activation of Gs-coupled adenosine receptors increases intracellular cAMP, we hypothesized that the inhibitory effects of adenosine on mast cells are mediated by the Gs-coupled adenosine receptors. In this study, we used both genetically modified animal models and mast cell cultures to comprehensively investigate the role of Gs-coupled adenosine receptors on mast cells both in vitro and in vivo. First, our data demonstrate a potent inhibitory effect of the nonhydrolyzable adenosine analog NECA on IgE-induced mast cell degranulation; this inhibitory effect of NECA was abolished by the genetic deletion of the A2B but ...
To our knowledge, this study is the first to report a regulatory function of tetraspanin CD151 in mast cells. Moreover, it is one of the first reports, to our knowledge, addressing the signaling mechanism of modulation of mast cell activation by any member of the tetraspanin family. In the present study, we demonstrated that CD151 deficiency exacerbated late-phase allergic inflammation in mice in vivo and enhanced proinflammatory cytokine production by cultured BMMCs ex vivo. Moreover, BMMCs deficient in CD151 showed enhanced and sustained FcεRI-induced ERK1/2 and Akt phosphorylation compared with WT cells. Conversely, CD151 deficiency had no effect on mast cell degranulation or the acute phase of PCA. Thus, our data demonstrate that the tetraspanin CD151 functions to selectively inhibit late-phase anaphylaxis responses and the de novo synthesis of cytokines by activated mast cells.. Mast cells possess mechanisms for fine tuning cellular activation that allow initial FcεRI-mediated signaling ...
Latexin, a protein possessing inhibitory activity against rat carboxypeptidase A1 (CPA1) and CPA2, is expressed in a neuronal subset in the cerebral cortex and cells in other neural and non-neural tissues of rat. Although latexin also inhibits mast-cell CPA (MCCPA), the expression of latexin in rat mast cells has not previously been confirmed. In the present study we examined the expression and subcellular localization of latexin in rat peritoneal mast cells. Western blot and reverse-transcriptase-mediated PCR analyses showed that latexin was contained and expressed in the rat peritoneal mast cells. Immunocytochemically, latexin immunofluorescence was localized on granular structures distinct from MCCPA-, histamine- or cathepsin D-immunopositive granules. Immunoelectron microscopy revealed that latexin was associated with a minority population of granules. The latexin-associated granules were separated from MCCPA- or histamine-containing granules on a self-generating density gradient of ...
Background and objective:Gingival bleeding reduction in smokers has been associated with decreased blood vessel density. The mechanism of suppressive effect of cigarette smoking on blood vessel density is not precisely defined. The aim of this study was to evaluate the impact of smoking on angiogenesis by assessing mast cells density and VEGF expression in chronic periodontitis. Materials& Methods: 52 paraffin embedded block of gingiva tissues with periodontitis obtained from 30 nonsmokers and 22 smokers undergoing flap surgery were examined immunohistochemically for VEGF expression. Mast cell counts was completed on toluidine blue stained slides. Exposure to cigarette smoking was calculated by the number of packs × year. Patients were classified into 4 groups based on the number of smoked cigarettes. The correlation between VEGF expression and mast cell counts was evaluated and compared in nonsmokers and smokers. Results: The mean number of mast cells (p=0.004) and average value of VEGF expression (p
Author(s): Hata, D; Kawakami, Y; Inagaki, N; Lantz, CS; Kitamura, T; Khan, WN; Maeda-Yamamoto, M; Miura, T; Han, W; Hartman, SE; Yao, L; Nagai, H; Goldfeld, AE; Alt, FW; Galli, SJ; Witte, ON; Kawakami, T | Abstract: We investigated the role of Brutons tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI
phdthesis{d683936c-1726-4ede-86a7-193f0162cd84, abstract = {Mast cell are found throughout the body, but are especially prominent in tissues that have direct contact with the external milieu such as the skin, gastrointestinal tract and lungs. Mast cells are commonly recognized for their detrimental role in allergic reactions and can, upon activation through the high-affinity receptor for IgE (FcεRI), rapidly produce and secrete many of the mediators responsible for the typical symptoms in urticaria, asthma and rhinitis. However, increasing amount of data show that mast cells have important, even vital, roles in host defence against bacteria, viruses, parasites and venoms. Mast cells exist as two different subtypes, MCT (mucosal mast cells) and MCTC (connective tissue mast cells). These two subtypes differ in their molecular expression and distribution in the body. MCT are for example the dominating subtype in the lungs, while MCTC are most common in the skin and the gastrointestinal tract. ...
Mast cells (MC) have been mainly studied as key effectors in allergic diseases and inflammatory conditions such hypersensitivity reactions, asthma, atopic dermatitis and multiple sclerosis. Following the crosslinkage of membraneous FcεRI, by antigens, a large number of chemical mediators are secreted. This event leads to the recruitment and activation of basophils and eosinophils that sustain the inflammatory response. The role of mast cells, however, is not limited to the initiation of allergic response but they are also fundamental players in the innate immune response; for example they can be activated directly by pathogens through a family of pattern recognition receptors called Toll-like receptors" (TLRs). In particular, TLR2 and 4 seem to be crucial to the mast cell response to pathogens. In rodents, mast cells respond to lipopolysaccharide through their TLR4s by the release of pro-inflammatory cytokines without concurrent degranulation or they can degranulate following peptidoglycan ...
TY - JOUR. T1 - Pediatric Expression of Mast Cell Activation Disorders. AU - Broesby-Olsen, Sigurd. AU - Carter, Melody. AU - Kjaer, Henrik Fomsgaard. AU - Mortz, Charlotte Gotthard. AU - Møller, Michael Boe. AU - Kristensen, Thomas Kielsgaard. AU - Bindslev-Jensen, Carsten. AU - Agertoft, Lone. PY - 2018/8. Y1 - 2018/8. N2 - Mast cell activation disorders is a term proposed to cover diseases and conditions related to activation of mast cells and effects of mast cell mediators. In its broadest sense, the term encompasses a wide range of diseases from allergic asthma to rhinoconjunctivitis, urticaria, food allergy, anaphylaxis, mastocytosis, and other conditions where MC activation is contributing to the pathogenesis. This article focuses on clinical presentations, challenges, and controversies in pediatric mastocytosis and gives an overview of current knowledge and areas in need of further research.. AB - Mast cell activation disorders is a term proposed to cover diseases and conditions related ...
Expression of Mast Cell Proteases Correlates with Mast Cell Maturation and Angiogenesis during Tumor Progression. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Mast cells donate to allergy through IgE-dependent activation the high-affinity IgE receptor FcεRI. receptor gain-of-function human mast cell line HMC-1. Unlike MS4A2 MS4A2trunc did not traffic to the cytoplasmic membrane but instead was associated with the nuclear membrane. Overexpression of MS4A2trunc induced human lung mast cell death and profoundly inhibited HMC-1 cell proliferation by inducing G2-phase cell cycle arrest and apoptosis. Thus we have identified a novel splice variant of MS4A2 that might be important in the regulation of human mast cell proliferation and survival. This finding demonstrates that the MS4A2 gene has multiple roles extending beyond the rules of acute sensitive reactions. By understanding the systems regulating its function it could be feasible to induce its manifestation in mast cells cells had been then transformed using the MS4A2 clones and plated from agar plates including 100 μg/ml ampicillin with 100 μl of IPTG and 20 μl of X-galactose added. Transformed ...
Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human
Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, which is characterized by inflammation of synovial joints leading to the destruction of cartilage and bone. Infiltrating mast cells can be found within the inflamed synovial tissue, however their role in disease pathogenesis is unclear. Therefore we have studied the role of mast cells during different phases of experimental arthritis. We induced collagen-induced arthritis (CIA), the most frequently used animal model of arthritis, in an inducible mast cell knock-out mouse and determined the effect of mast cell depletion on the development and severity of arthritis. Depletion of mast cells in established arthritis did not affect clinical outcome. However, depletion of mast cells during the preclinical phase resulted in a significant reduction in arthritis. This reduction coincided with a decrease in circulating CD4+ T cells and inflammatory monocytes but not in the collagen-specific antibody levels. Mast cell depletion resulted in reduced
In addition to their central role in allergy, mast cells are involved in a wide variety of cellular interactions during homeostasis and disease. In this review, we discuss the ability of mast cells to extend their mechanisms for intercellular communication beyond the release of soluble mediators. These include formation of mast cell synapses on antigen presenting surfaces, as well as cell-cell contacts with dendritic cells and T cells. Release of membrane bound exosomes also provide for the transfer of antigen, mast cell proteins, and RNA to other leukocytes. With the recognition of the extended role mast cells have during immune modulation, further investigation of the processes in which mast cells are involved is necessary. This reopens mast cell research to exciting possibilities, demonstrating it to be an immunological frontier ...
TY - JOUR. T1 - BLT2 is upregulated in allergen-stimulated mast cells and mediates the synthesis of Th2 cytokines. AU - Cho, Kyung Jin. AU - Seo, Ji Min. AU - Lee, Min-Goo. AU - Kim, Jae-Hong. PY - 2010/11/15. Y1 - 2010/11/15. N2 - Mast cells are effector cells that mediate the allergic response through Ag stimulation of IgE bound to FcεRI. In allergic reactions, cross-linking of the surface receptors for IgE on mast cells results in the synthesis of Th2 cytokines such as IL-4 and IL-13, which are critical for the initiation and progression of the allergic response. Despite the important roles of these cytokines, the signaling mechanism by which Ag stimulation mediates the production of IL-4 and IL-13 in mast cells is not clearly understood. In the present study, we found that Ag-stimulated bone marrow-derived mast cells (BMMCs) highly upregulated the expression of BLT2, a leukotriene B 4 receptor, and that blockade of BLT2 with the specific antagonist LY255283 or small interfering RNA ...
Mast cell (MC) differentiation, survival, and activation are controlled by the membrane tyrosine kinase c-Kit upon interaction with stem cell factor (SCF). Here we describe a single point mutation induced by N-ethyl-N-nitrosurea (ENU) mutagenesis in C57BL/6J mice-an A to T transversion at position 2388 (exon 17) of the c-Kit gene, resulting in the isoleucine 787 substitution by phenylalanine (787F), and analyze the consequences of this mutation for ligand binding, signaling, and MC development. The Kit(787F/787F) mice carrying the single amino acid exchange of c-Kit lacks both mucosal and connective tissue-type MCs. In bone marrow-derived mast cells (BMMCs), the 787F mutation does not affect SCF binding and c-Kit receptor shedding, but strongly impairs SCF-induced cytokine production, degranulation enhancement, and apoptosis rescue. Interestingly, c-Kit downstream signaling in 787F BMMCs is normally initiated (Erk1/2 and p38 activation as well as c-Kit autophosphorylation) but fails to be ...
Mast cells are tissue-resident hematopoietic cells. Because infectious agents enter the host through environmentally exposed barriers, such as the skin, gastrointestinal tract, and respiratory tract, mast cells are poised to be one of the first cell types to respond to invading pathogens. Furthermore, mast cells express a wide array of pattern recognition receptors that endow them with the ability to respond to a broad range of stimuli, such as infections and pathogenic conditions (51). It is well established that mast cells play crucial immune surveillance roles during bacterial and parasitic infections (8, 12). In contrast, the role of mast cells in the immune surveillance of viral infections has received less attention. In the current study, we examined the role of mast cells in sensing IAV infection and initiating the subsequent inflammatory response.. A primary rationale for our work stems from the recent work by Teijaro et al. (6), who demonstrated that blunting the cytokine storm ...
TY - JOUR. T1 - Novel Site-Specific Mast Cell Subpopulations in the Human Lung.. AU - Andersson, Cecilia K. AU - Mori, Michiko. AU - Bjermer, Leif. AU - Löfdahl, Claes-Göran. AU - Erjefält, Jonas. PY - 2009. Y1 - 2009. N2 - BACKGROUND: Lung mast cells are stereotypically divided into connective tissue (MCTC) and mucosal (MCT) mast cells. This study tests the hypothesis that each of these subtypes can be divided further into site-specific populations created by the microenvironment within each anatomic lung compartment. METHODS: To study mast cells under non-inflamed conditions surgical resections and bronchial and transbronchial biopsies from non-smoking individuals were obtained to investigate morphometric and molecular characteristics of mast cell populations in multiple lung structures by immunohistochemistry and electron microscopy. RESULTS: MCT and MCTC coexisted at all compartments with MCT being the prevailing type in bronchi, bronchioles and the alveolar parenchyma. MCTC were more ...
T cell mediated immune responses in the gut can produce enteropathy and malabsorption. We have investigated the relevance of mucosal mast cells (MMC) to the mechanisms of this enteropathy by using graft-versus-host reaction (GvHR) in the rat as a model of mucosal delayed type hypersensitivity. Measurements of mucosal architecture, intraepithelial lymphocytes (IEL) and MMC counts were performed in control and experimental rats, and release of rat mast cell protease II (RMCPII) into the bloodstream was used as an index of MMC activation. In unirradiated rats, jejunal MMC count was increased on day 14 of the GvHR (mean 272/mm2 v 182 in controls, p less than 0.01), as was serum RMCPII (p less than 0.01). Irradiated rats (4.5 Gy, reconstituted with isogeneic spleen cells) had low counts of IEL and crypt hyperplasia seven to 14 days after irradiation. Irradiated rats with GvHR (induced by ip injection of parental strain spleen cells) and studied on days 7, 10 and 14, had significant enteropathy with ...
Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase ...
METHODS AND RESULTS Specimens of normal and atherosclerotic human coronary intima from 32 autopsy cases with ages ranging from 13 to 67 years were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase. Of the tryptase-containing mast cells, a variable proportion (average, 40%; range, 0% to 100%) also contained chymase. In the normal coronary intimas, mast cells amounted to 0.1% of all nucleated cells. In the fatty streaks, this proportion was higher by 9-fold, and in the cap, core, and shoulder regions of atheromas by 5-, 5-, and 10-fold, respectively. Electron and light microscopic studies of mast cells in the shoulder region of atheromas revealed degranulation of mast cells, a sign of their activation, and moreover, that the proportion of activated mast cells was much higher (85%) in this region than in the normal intima (18%). ...
Mast cells are abundantly expressed in synovial tissues and have been proposed to exert proinflammatory effects primarily based on antibody transfer-induced disease models (28, 29). The mode of mast cell activation and the mechanism by which activated-mast cells mediate antigen-induced arthritis are largely unknown and likely complex. We now provide direct in vivo evidence that IL-33 plays a major role in mast cell activation in the context of antigen-induced arthritis. Thus, IL-33 enhanced CIA when ST2−/− mice were reconstituted with BMMCs from WT but not from ST2−/− mice (Fig. 5). Our data also provide mechanisms by which mast cells could promote inflammatory synovitis (Fig. 6). IL-33 induces mast cell production of IL-1, IL-6, IL-13, and a range of chemokines (13, 14, 30) (Fig. 4). Because both IL-1 and IL-6 play crucial roles in the induction of Th17 cells (31-33), a key pathogenic cell type in arthritis (21, 22), our studies indicate a relationship between ST2/IL-33 function and ...
The mast cell possesses within itself granules of especially inflammatory biochemicals meant for use against invading parasites. (Think of these as small bombs that can be released). The mast cell has binding sites on its surface for a special type of antibody called IgE. IgE is produced in response to exposure to antigens typical of parasites (i.e., worm skin proteins, or similarly shaped proteins). IgE antibodies, which are shaped like tiny Ys, find their way to a tissue mast cell and perch there. With enough exposure to the antigen in question, the mast cell may be covered with Y- shaped IgE antibodies like the fluff of a dandelion. The mast cell is said, at this point, to be sensitized ...
The mast cell possesses within itself granules of especially inflammatory biochemicals meant for use against invading parasites. (Think of these as small bombs that can be released). The mast cell has binding sites on its surface for a special type of antibody called IgE. IgE is produced in response to exposure to antigens typical of parasites (i.e., worm skin proteins, or similarly shaped proteins). IgE antibodies, which are shaped like tiny Ys, find their way to a tissue mast cell and perch there. With enough exposure to the antigen in question, the mast cell may be covered with Y- shaped IgE antibodies like the fluff of a dandelion. The mast cell is said, at this point, to be sensitized ...
TY - JOUR. T1 - ATP-induced pore formation in the plasma membrane of rat peritoneal mast cells. AU - Hofmann, Polly. AU - Metzger, Joseph M.. AU - Greaser, Marion L.. AU - Moss, Richard L.. PY - 1990/3/1. Y1 - 1990/3/1. N2 - Various functional roles for myosin light chain 2 (LC2) have been suggested on the basis of numerous and predominantly in vitro biochemical studies. Using skinned fibers from rabbit psoas muscle, the present study examines the influence of partial removal of LC2 on isometric tension, stiffness, and maximum velocity of shortening at various levels of activation by Ca2+. Isometric tension, stiffness, and velocity of shortening were measured at pCa values between 6.6 and 4.5 (a) in a control fiber segment, (b) in the same fiber segment after partial removal of LC2, and (c) after recombination with LC2. The extraction solution contained 20 mM EDTA, 20 or 50 mM KC1, and either imidazole or PO4 2− as a pH buffer (pH 7.0). The amount of LC2 extracted varied with the temperature, ...
Mast cells play a central role in the pathogenesis of allergic reaction. Activation of mast cells by antigens is strictly dependent on the influx of extracellular calcium that involves a complex interaction between signalling molecules located within the cells. We have previously reported that tHGA, an active compound originally isolated from a local shrub known as Melicope ptelefolia, prevented IgE-mediated mast cell activation and passive systemic anaphylaxis by suppressing the release of interleukin-4 (IL-4) and tumour necrosis factor (TNF)-α from activated rat basophilic leukaemia (RBL)-2H3 cells. However, the mechanism of action (MOA) as well as the molecular target underlying the mast cell stabilising effect of tHGA has not been previously investigated. In this study, DNP-IgE-sensitised RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA. To dissect the MOA of tHGA in IgE-mediated mast cell activation, the effect of tHGA on the transcription of IL-4 and TNF-α mRNA was ...
With regard to mast cells, Im always looking at mesenchymal and histiocytic tumors of human skin and in my experience dendritic connective tissue mast cells also stain for CD68 (KP-1) a lysosomal glycoprotein. In fact, Im having to do toluidine blue (which gets most of the stromal mast cells,no?) to distinguish these from the histiocytes (some CD68+) and dermal dendritic cells (CD68 negative) in a series of histiocytomas. Havent noticed many mucosal (epithelial?) mast cells in skin though. I like to use end mounted individual controls. For our commonly performed stains, (like alcian blue on Gastroesophageal junction and esophagus, iron, PAS, mucin. etc, I choose a block from that days work, (eg a small colon polyp for alcian blue/muci) and pickup some extra sections. That way, I can pick up a section on the end of each special slide,each has its own control. I also keep common control blocks handy and do this with ER/PR/Her 2 neu, iron, retic, fungus etc. Mine is a one person lab so the ...
The á2â1 integrin is expressed on many cell types throughout the immune system. Expression of the á2â1 integrin on mast cells is required for the early innate immune response to Listeria monocytogenes. Interaction between the á2â1 integrin and Listeria occurs through C1q within a Listeria immune complex, but is not sufficient for activation suggesting an additional co-receptor is required for activation. We demonstrate that Listeria immune complex activation of mast cells occurs through crosstalk between the á2â1 integrin and c-met. The best described mechanism of mast cell activation is IgE-mediated degranulation. We examined the mechanism of mediator release by mast cells following activation by Listeria immune complex. Activation by Listeria immune complex results in á2â1 integrin-dependent release of IL-6 from a granule pool that is distinct from known mast cell granules, identifying a novel population of mast cell granules. The á2â1 integrin-dependent early innate immune ...
Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel Fc epsilon RI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.. ...
Dr. Dean Metcalfe, Head of the Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD, USA Coffee is served 15:00. Welcome! About Dean Metcalfe Dr. Metcalfe is a world leading scientist, particularly in the field of mast cell biology and mast cell functions related to human disease. He has published more than 500 scientific papers, including several seminal publications.
Conclusions Good compliance with UK guidelines for tryptase measurements is achievable in this long-term cohort, but obtaining clinical details at referral remains a challenge. Sample sequence labelling and apparent timing may be misleading. Baseline tryptase may frequently need to be rechecked in allergy clinics to estimate true peak-to-trough changes. ...
Molecular regulation of mast cell development and maturation.: Mast cells play a crucial role in the pathogenesis of allergic diseases. In recent years, tremend
Background: Heparanase degradation of heparan sulfate plays important roles in a number of pathological processes, including inflammation. In vitro experiments show that heparanase is capable of degrading heparin, a polysaccharide present in mast cells (MCs), in which it has a key role in promoting the storage of secretory granule compounds.. Objective: We sought to investigate the functions of heparanase in MCs.. Methods: Primarily cultured fetal skin-derived mast cells (FSMCs) isolated from embryos and adult peritoneal MCs were analyzed for storage and release of granule molecules in response to MC activation.. Results: FSMCs from heparanase-overexpressing mice contained substantially shorter heparin chains and significantly less proteases than control cells. Conversely, FSMCs lacking heparanase contained heparin of larger size and more proteases than control cells. Correspondingly, heparanase-overexpressing adult MCs exhibited reduced release of heparin-bound proteases, a finding that could ...
A mast cell tumor (MCT) is caused by the over-proliferation of neoplastic mast cells. Mast cells are normally found in the skin and many other tissues such as lymph nodes as part of the immune system. The most common sites for MCT in the cat are the skin, subcutaneous tissues, and the spleen.. In order to assess severity of disease, bloodwork and an abdominal ultrasound was performed on Penelope. Thankfully, no signs of visceral MCT was present and she was diagnosed with cutaneous localized disease. Surgery was performed to remove the mass and clean surgical margins were achieved giving Penelope a good prognosis and small chance of recurrence.. This case illustrates the importance diagnostics when it comes to cutaneous skin masses. When a patient presents with a skin or subcutaneous mass, it is impossible to eliminate the chance of a patient having a mast cell tumor based on palpation and appearance alone. They can be haired or hairless, ulcerated or smooth, singular or in groups and are ...
Mastocytosis is a disease characterized by mast cell invasion in various organs. Mast cells are bone marrow derived cells which produce histamine and other substances causing allergic and anaphylactic reactions. Accumulation of mast cells in body organs can inhibit the functionality of the organ and eventually cause degeneration.. Mutations of the mast cell growth factor receptor (KIT protein, the product of the c-Kit proto-oncogene) might be found in patients with mastocytosis.. Masitinib (AB1010) is a tyrosine kinase inhibitor (TKI), selectively and effectively inhibiting c-kit. Its effect may include inhibition of cell proliferation, inhibition of cell cycle progression and induction of apoptosis resulting in the reduction of mast cell accumulation in body tissues. This drug is thereby specific to mastocytosis and active in slowing or reducing the number of mast cells particularly in aggressive forms of the disease. ...
Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented ...