Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence suggests that allergy is a significant triggering factor in asthma in children and adults alike. In immunoglobulin (Ig) E-mediated allergic reactions, sensitization occurs when allergen-specific B cells are stimulated and switched to IgE antibody production by interleukin (IL)-4 and IL-13 provided by helper T cells type 2 (Th2). The IgE antibodies act by arming cells bearing either the high-affinity (FcepsilonRI) or low-affinity (FcepsilonRII or CD23) receptor. The subsequent interaction of allergen with IgE-FcepsilonRI complexes on mast cells and basophils causes cross-linking of receptors that triggers the release of a variety of inflammatory mediators, cytokines and chemokines. Therefore, the ability to lower circulating free IgE levels is desirable because most individuals are exposed to multiple allergens to which they are sensitive at any given time. Omalizumab (formerly known as rhuMAb-E25) is a recently developed humanized monoclonal anti-IgE antibody directed at the FcepsilonRI binding domain of human IgE. It inhibits binding of IgE to mast cells without provoking mast cell activation. Preliminary clinical data from randomized controlled trials have shown that the addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use. The compound is also well tolerated. Omalizumab represents a novel therapeutic approach in the management of asthma.
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PMID:Allergens in the pathogenesis of asthma: potential role of anti-immunoglobulin E therapy. 1472 38

The future management of patients with allergic asthma is poised to change in the coming one to two decades. This prediction is based on fundamental new insights into the pathogenesis of disease, gained through the study of both humans and experimental models of asthma. These studies have revealed that allergic asthma is an immune-mediated disease which, despite the redundancy characteristic of all immune responses, may be induced through a single dominant signaling cascade called the interleukin (IL)-4/IL-13 signaling pathway. In addition to the cytokine IL-4, this pathway includes IL-13, the cytokine receptor subunit IL-4 receptor alpha (IL-4Ralpha), Janus-associated tyrosine kinases and the transcription factor, signal transducer and activator of transcription 6. The IL-4 signaling pathway controls the most important cellular developmental (afferent) events that underlie asthma. These include T helper (Th) type 2 cell activation, B cell activation and immunoglobulin (Ig) E secretion, mast cell development, and effector (efferent) events related exclusively to immune effects on the lung such as goblet cell metaplasia and airway hyperresponsiveness. Any of the IL-4 signaling molecules are potentially amenable to pharmacological intervention, but a detailed understanding of the entire pathway is required to appreciate their actual potential for drug development. For example, neutralization strategies that target only IL-4 are unlikely to succeed because they leave IL-13 free to continue the signaling cascade. In contrast, neutralization of IL-4Ralpha may represent a more feasible strategy, as it should prevent signaling by both IL-4 and IL-13. The therapeutic potential of targeting intracytoplasmic tyrosine kinases has already been achieved with the use of small molecules, suggesting that this approach may be realistically adopted for the treatment of asthma. However, well designed asthma clinical trials are warranted to determine with certainty, the efficacy of therapies based on IL-4/IL-13 blockade.
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PMID:Biology and therapeutic potential of the interleukin-4/interleukin-13 signaling pathway in asthma. 1472 56

Asthma is a common, chronic inflammatory condition of the airways that leads to airway hyperresponsiveness, reversible narrowing of the airways, and airway wall remodeling. Cytokines are involved in various aspects of asthma pathophysiology, such as the polarization of T-helper (Th)2 cells, antigen presentation, immunoglobulin (Ig)E response, airway wall remodeling, and mast cell and eosinophil recruitment and activation. Th2-derived cytokines, such as interleukin (IL)-4, IL-5 and IL-13 contribute to many of these aspects. Inhibition of individual cytokines for asthma therapy has been, and continues to be investigated. Anti-IL-5 monoclonal antibodies did not demonstrate beneficial effects in asthma, with only partial inhibition of eosinophilia in the airway wall; soluble IL-4 receptor, which neutralizes the effects of IL-4, has provided modest improvements in moderate asthma. The anti-IgE monoclonal antibody approach has demonstrated the most benefit in allergic asthma, particularly in severe disease. Which individual cytokine target can be inhibited with beneficial effects comparable to or above that of current inhaled corticosteroids can only be discovered through clinical trials. Blocking the effects of more than one cytokine may be more successful, and greater therapeutic effects may be observed in particular categories of asthma.
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PMID:Individual cytokines contributing to asthma pathophysiology: valid targets for asthma therapy? 1475 71

Two distinct pathways of anaphylaxis in the mouse have similar clinical features: the classical pathway in which antigen cross-linking of IgE bound to FcepsilonRI on mast cells induces histamine release, and a second pathway, in which cross-linking of macrophage FcgammaRIII by antigen-IgG complexes induces release of platelet activating factor. IgG antibodies are a double-edged sword, blocking the first pathway but mediating the second. Both anaphylaxis pathways are considerably enhanced by interleukin (IL)4 or IL13 through a Stat6-dependent, gammac-independent mechanism. Enhancement is rapid, sensitive, and observed during infection with intestinal nematode parasites, where it probably contributes to parasite expulsion. Enhancement involves increased sensitivity to mediators (platelet activating factor, histamine, serotonin, and cysteinyl leukotrienes), rather than increased mediator production, and is mediated by a synergistic increase in vascular permeability by cytokine plus mediator. Basophil production of IL4 and IL13, which is more sensitive to FcepsilonRI cross-linking than mast cell release of mediators, may sensitize target cells to mediators prior to their release. Inhibitors of IL4 and IL13 may ameliorate allergy by rapidly blocking the sensitizing effects of these cytokines on the effector phase of the allergic response, as well as by more slowly blocking the induction phase of this response.
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PMID:Cytokine enhancement of anaphylaxis. 1502 93

Recent studies have revealed that murine bone marrow-derived cultured mast cells (BMMC), which are phenotypically immature mast cells, express functional TLR2 and TLR4 that recognize distinct pathogen-associated molecules. However, it remains relatively uncertain whether mast cells express other TLR. We recently established a method to obtain large numbers of murine fetal skin-derived cultured mast cells (FSMC); these cells exhibit important features of connective tissue type mast cells. Working with FSMC and BMMC, the TLR mRNA expression profiles were compared between both cell types. Although TLR2 and TLR4 mRNA were detected in both cells at comparable levels, TLR3, TLR7, and TLR9 mRNA were expressed by FSMC at higher levels than by BMMC, suggesting distinct TLR expression profiles among different mast cell populations. With respect to their functional aspects, FSMC, but not BMMC, dose dependently produced proinflammatory cytokines (TNF-alpha and IL-6) and chemokines (RANTES, MIP-1alpha, and MIP-2) in response to poly(I:C), R-848, and CpG oligodeoxynucleotide, which are TLR3, TLR7, and TLR9 activators, respectively. Interestingly, these TLR activators failed to induce degranulation and IL-13 production by both mast cells, although peptidoglycan and LPS (TLR2 and TLR4 activators, respectively) induced IL-13 production by both cells. Mast cells, thus, may have potential to recruit other immune cells to the infected sites by responding to various bacterial and viral components through TLR signaling pathways, presumably being involved in initiating innate immunity and subsequently linking innate and acquired immune responses.
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PMID:TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. 1521 Aug 14

Intestinal worm infections characteristically induce T-helper 2 cell (Th2) cytokine production. We reviewed studies performed with mice infected with either of two intestinal nematode parasites, Nippostrongylus brasiliensis or Trichinella spiralis, that evaluate the importance of the Th2 cytokine interleukin-4 (IL-4) and IL-13 in protection against these parasites. These studies demonstrate that while IL-4/IL-13 protect against both parasites by activating signal transducer and activator of transcription 6 (Stat6) through IL-4 receptor alpha (IL-4Ralpha) ligation, Stat6 activation protects against these parasites through different mechanisms. Stat6-dependent gene transcription promotes expulsion of N. brasiliensis solely through effects on non-bone marrow-derived cells that may include enhancement of intestinal smooth muscle contractility, changes in intestinal epithelial cell function, and increased intestinal mucus secretion. In contrast, Stat6 signaling promotes immunity to T. spiralis both through effects on bone marrow-derived cells that can be reproduced by treating mice with IL-4 or IL-13 and through effects on non-bone marrow-derived cells. The former effects appear to include T-cell-dependent induction of intestinal mastocytosis, while the latter sensitize non-bone marrow-derived cells to mast cell-produced mediators. We argue that a limited ability of the host immune system to distinguish among different nematode parasites has led to the evolution of a stereotyped Th2 response that activates a set of effector mechanisms that protects against most intestinal nematode parasites.
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PMID:Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. 1536 Dec 38

To address the role played by MD-2 in mast cell recognition of LPS, we examined bone marrow-derived mast cells (BMMCs) from MD-2 gene-targeted mice. BMMCs from MD-2-/- mice showed impaired cytokine production (TNF-alpha, IL-6, IL-13, and IL-1beta) in response to LPS from Escherichia coli, but not to peptidoglycan (PGN) from Staphylococcus aureus. In a mast cell-dependent acute septic model, MD-2 deficiency of mast cell resulted in significantly higher mortality due to defective neutrophil recruitment and the production of cytokines in the peritoneal cavity, which was similar to mice with TLR4-deficient mast cells. The TLR2-dependent activation of skin mast cells by PGN was not altered by the absence of MD-2 in vivo. Collectively, MD-2 is essential for the recognition of LPS by TLR4 but not for that of PGN by TLR2 of mast cells.
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PMID:MD-2 is required for the full responsiveness of mast cells to LPS but not to PGN. 1536 78

Diesel exhaust (DE) is a major component of airborne particulate matter. In previous studies we have described the acute inflammatory response of the human airway to inhaled DE. This was characterized by neutrophil, mast cell, and lymphocyte infiltration into the bronchial mucosa with enhanced epithelial expression of IL-8, Gro-alpha, and IL-13. In the present study, we investigated whether redox-sensitive transcription factors were activated as a consequence of DE exposure, consistent with oxidative stress triggering airway inflammation. In archived biopsies from 15 healthy subjects exposed to DE [particulates with a mass median diameter of <10 mum, 300 microg/m3] and air, immunohistochemical staining was used to quantify the expression of the transcription factors NF-kappaB (p65) and AP-1 (c-jun and c-fos), as well their upstream MAPKs, p38 and JNK, in the bronchial epithelium. In addition, phosphorylation of tyrosine residues was examined. DE induced a significant increase in the nuclear translocation of NF-kappaB (P = 0.02), AP-1 (P = 0.02), phosphorylated JNK (P = 0.04), and phosphorylated p38 (P = 0.01), as well as an increase in total (cytoplasmic + nuclear) immunostaining of phosphorylated p38 (P = 0.03). A significant increase in nuclear phosphorylated tyrosine was also observed (P < 0.05). These observations demonstrate that DE activates redox-sensitive transcription factors in vivo consistent with oxidative stress triggering the increased synthesis of proinflammatory cytokines.
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PMID:Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways. 1621 22

Studies with murine models demonstrate 2 pathways of systemic anaphylaxis: one mediated by IgE, Fc epsilonRI, mast cells, histamine, and platelet-activating factor (PAF), and the other mediated by IgG, Fc gammaRIII, macrophages, and PAF. The former pathway requires much less antibody and antigen than the latter. As a result, IgG antibody can block IgE-mediated anaphylaxis induced by small quantities of antigen without mediating Fc gammaRIII-dependent anaphylaxis. The IgE pathway is most likely responsible for most human anaphylaxis, which generally involves small amounts of antibody and antigen; similarities in the murine and human immune systems suggest that the IgG pathway might mediate disease in persons repeatedly exposed to large quantities of antigen. Mice, like human subjects, can experience IgE/Fc epsilonRI/mast cell-mediated gastrointestinal and systemic anaphylaxis in response to ingested antigen. Gastrointestinal symptoms depend on serotonin and PAF; mediator dependence of systemic symptoms has not been determined. Both local and systemic anaphylaxis induced by ingested antigens might be blocked by IgA and IgG antibodies. IL-4 and IL-13 signaling through the IL-4 receptor alpha chain, in addition to promoting the mastocytosis and IgE antibody production that mediate most human anaphylaxis, exacerbates the effector phase of anaphylaxis by increasing target cell responsiveness to vasoactive mediators. As a result, IL-4 receptor alpha chain antagonists might be particularly effective suppressors of anaphylaxis.
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PMID:Molecular mechanisms of anaphylaxis: lessons from studies with murine models. 1575 6

Extracellular ATP and other nucleotides act through specific cell surface receptors and regulate a wide variety of cellular responses in many cell types and tissues. In this study, we demonstrate that murine mast cells express several P2Y and P2X receptor subtypes including P2X(7), and describe functional responses of these cells to extracellular ATP. Stimulation of bone marrow-derived mast cells (BMMC), as well as MC/9 and P815 mast cell lines with millimolar concentrations of ATP, resulted in Ca(2+) influx across the cellular membrane and cell permeabilization. Moreover, brief exposures to ATP were sufficient to induce apoptosis in BMMCs, MC/9, and P815 cells which involved activation of caspase-3 and -8. However, in the time period between commitment to apoptosis and actual cell death, ATP triggered rapid but transient phosphorylation of multiple signaling molecules in BMMCs and MC/9 cells, including ERK, Jak2, and STAT6. In addition, ATP stimulation enhanced the expression of several proinflammatory cytokines, such as IL-4, IL-6, IL-13, and TNF-alpha. The effects of ATP were mimicked by submillimolar concentrations of 3-O-(4'-benzoyl)-benzoyl-benzoyl-ATP, and were inhibited by pretreatment of mast cells with a selective blocker of human and mouse P2X(7) receptor, 1[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine, as well as oxidized ATP. The nucleotide selectivity and pharmacological profile data support the role for P2X(7) receptor as the mediator of the ATP-induced responses. Given the importance of mast cells in diverse pathological conditions, the ability of extracellular ATP to induce the P2X(7)-mediated apoptosis in these cells may facilitate the development of new strategies to modulate mast cell activities.
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PMID:Extracellular ATP induces cytokine expression and apoptosis through P2X7 receptor in murine mast cells. 2128 17


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