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

Anti-receptor antibodies have previously been used in two cytokine systems (IL-1 and TNF alpha) to identify the existence of different cytokine receptors on different cell types. In this study, we have similarly used two approaches to evaluate whether IL-4 receptors on different cell types are identical, or whether more than one species of IL-4 receptor exists. The first approach involved production of monoclonal antibodies specific for the IL-4 receptor expressed by the murine mast cell line, MC/9. Six anti-IL-4 receptor monoclonal antibodies were produced against the purified soluble extracellular domain of the recombinant IL-4 receptor derived from MC/9 cells. These antibodies were capable of binding to and specifically immunoprecipitating the soluble extracellular domain of the recombinant mast cell IL-4 receptor. Following biotinylation of the antibodies and addition of phycoerythrin-streptavidin, their binding to cell associated IL-4 receptors on MC/9 mast cells could be readily visualized by immunofluorescence. Using this approach, the anti-mast cell IL-4R antibodies were found to specifically bind IL-4 receptors expressed on a variety of other murine cell types, including T cells, B cells, macrophages, fibroblasts, and L cells. The antibodies did not bind to two human cell lines known to bind human but not murine IL-4. The intensity of staining was directly related to the number of IL-4 binding sites identified previously by receptor-ligand equilibrium binding analyses. As a second approach to evaluating potential receptor heterogeneity, we constructed S1 nuclease protection assay probes for two separate regions of the mast cell IL-4 receptor, one located in the extracellular domain and one in the intracellular domain. Subsequent S1 analyses showed that both regions are expressed by the following types of cells: T cells, B cells, macrophages, myeloid cells, L cells, and stromal cells. The two approaches used in this study therefore indicate that the same or highly similar IL-4 receptor species is expressed by a wide variety of hemopoietic and nonhemopoietic cells. Since the anti-IL-4 receptor antibodies produced in this study did not block binding of IL-4 to its receptor, we cannot exclude the possible existence of a second type of IL-4R coexpressed on the cells tested in this study, or expressed uniquely by other cell types that were not investigated.
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PMID:Evaluation of murine interleukin 4 (IL-4) receptor expression using anti-receptor monoclonal antibodies and S1 nuclease protection analyses. 206 18

We have recently demonstrated that c-fes protooncogene product (FES), or a FES-related protein, associates with the interleukin-4 receptor alpha chain (IL-4R alpha) and phosphatidylinositol-3 (PI3) kinase in mouse T cell lines; however, others have demonstrated that PI3 kinase associates with IL-4R alpha through tyrosine phosphorylated insulin receptor substrate (IRS)-2 in other cell types. In order to examine whether IL-4 activates these two distinct PI3 kinase pathways in the same cells, we analyzed association of PI3 kinase with IRS-2, and tyrosine phosphorylation of IRS-2, in a mouse pro-B cell line, Ba/F3, and a mouse mast cell line, MC9. In both cell lines, IL-4 induced tyrosine phosphorylation of IRS-2, association of PI3 kinase with IRS-2, and FES or a FES-related protein. These results indicate that IL-4 activates two distinct PI3 kinase pathways in the same cells. We further identified the critical region in the cytoplasmic domain of IL-4R alpha required for tyrosine phosphorylation of IRS-2.
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PMID:Interleukin-4 activates two distinct pathways of phosphatidylinositol-3 kinase in the same cells. 895 48

Reorganization of the extracellular matrix is important in many biological and pathophysiological processes, including tissue remodelling, wound healing, or cancer metastasis. The ability of cultured fibroblasts to reorganize and contract three-dimensional type I collagen gels is regarded as an in vitro model for this process. In tissue fibrosis, complex interactions among fibroblasts, inflammatory cells and the extracellular matrix are taking place. Mast cells have often been discussed to play a role in several fibrotic conditions including scleroderma, scar formation, or wound healing. In this study, we examined the effects of mast cells on contraction of collagen lattices. The results demonstrate that co-culture of dermal fibroblasts with a human mast cell line (HMC-1) significantly enhanced contraction of the three-dimensional collagen lattices, whereas mast cells alone failed to contract the gel. Addition of culture supernatants of mast cells did not enhance the speed of gel contraction, indicating the importance of cell-cell contact. Morphological analysis showed that mast cells were incorporated into the lattices. Histological examination also demonstrated that within the lattices, mast cells were localized in close contact to, or attached to, fibroblasts. As fibroblasts and mast cells are known to attach via stem cell factor (SCF)/c-kit interaction when co-cultured in monolayers, we also examined the effect of antibodies against SCF and c-kit in this system. Addition of both antibodies inhibited gel contraction up to 70%. In contrast, antibodies against interleukin-4 (IL-4) and IL-4 receptor did not affect gel contraction. These results indicate that mast cells enhance fibroblast-mediated contraction of collagen lattices via direct cell-cell contact, mediated in part by SCF/c-kit interactions.
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PMID:Mast cells enhance contraction of three-dimensional collagen lattices by fibroblasts by cell-cell interaction: role of stem cell factor/c-kit. 1071 74

Gain-of-function mutations in c-kit, which appear to contribute to mast cell hyperplasia, have been detected in both limited and aggressive forms of mastocytosis, suggesting that other mutations or polymorphisms may contribute to the clinical phenotype. Because addition of interleukin-4 (IL-4) to mast cell cultures is reported to induce apoptosis, the hypothesis was considered that individuals carrying the gain-of-function polymorphism Q576R in the cytoplasmic domain of the alpha-subunit of the IL-4 receptor (IL-4R) might be relatively resistant to the gain-of-function mutation in c-kit. To assess this possibility, 36 patients with either cutaneous or systemic mastocytosis were studied for association with the Q576R polymorphism. The Q576R polymorphism was found more frequently in those with disease limited to skin and who exhibited lower levels of surrogate disease markers. These data suggest that the Q576R IL-4R alpha- chain polymorphism may mitigate disease expression and confer a better prognosis in patients with mastocytosis. (Blood. 2001;98:880-882)
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PMID:Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin. 1146 92

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

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

SHP-1 has been shown to play positive and negative regulatory roles in IL-4-induced STAT6 phosphorylation and in IL-4-mediated functions. To determine whether SHP-1 can regulate STAT6 phosphorylation and IL-4-mediated functions in a cell type-specific manner in the immune system, we examined the IL-4 receptor (IL-4R) expression, STAT6 phosphorylation, and IL-4-mediated functions in CD4+ and CD8+ T cells of viable motheaten (me(v)/me(v)) and littermate control (+/-) mice. CD4+ T cells as well as CD8+ T cells from the lymph node of me(v)/me(v) and +/- mice expressed comparable levels of IL-4R. In CD4+ T cells, the loss of SHP-1 activity did not affect IL-4-induced STAT6 phosphorylation or IL-4-mediated function. In contrast, SHP-1-deficient CD8+ T cells from me(v)/me(v) mice failed to develop into IL-4-producing type-2 cytotoxic T cells (Tc2) in the presence of IL-4 despite that they showed comparable levels of STAT6 phosphorylation to that of +/- CD8+ T cells. Loss of SHP-1 activity also abolished IL-4-mediated inhibition of c-kit expression in bone marrow-derived mast cell (BMMC). Thus, our data suggest that SHP-1 may regulate IL-4-induced STAT6 phosphorylation and IL-4-mediated functions in a cell type-specific manner.
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PMID:SHP-1 regulates STAT6 phosphorylation and IL-4-mediated function in a cell type-specific manner. 1561 79

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

Individuals with food allergy often present with uritcaria and atopic dermatitis. Indeed, susceptibility to food allergy may predispose to the development of these cutaneous allergic disorders. Recently, we developed a model of food allergy, whereby oral consumption of food [pea Pisum sativum L.; expressing alpha-amylase inhibitor-1 (alphaAI) from the common bean Phaseolus vulgaris L. cv Tendergreen (pea-alphaAI)] promotes a T helper cell type 2 (Th2) inflammatory response and predisposes to cutaneous allergic reactions following subsequent food allergen (alphaAI) exposure. To delineate the kinetics of food allergen-induced cutaneous reactions and examine the inflammatory mechanisms involved in this allergic reaction, we used interleukin (IL)-13-, IL-4 receptor alpha-, and eotaxin-1-deficient mice and performed serum transfer and CD4+ T cell depletion studies. We demonstrate that consumption of pea-alphaAI promotes an alphaAI-specific immunoglobulin G1 (IgG1) and IgE antibody response. Furthermore, we show that subsequent food allergen (alphaAI) challenge in the skin induced an early (3 h)- and late-phase (24 h) cutaneous allergic reaction. The early-phase response was associated with mast cell degranulation and the presence of Ig, whereas the late-phase response was characterized by a lymphoid and eosinophilic infiltrate, which was critically regulated by CD4+ T cells, IL-13, and eotaxin-1. Collectively, these studies demonstrate that food allergy can predispose to cutaneous inflammatory reactions, and these processes are critically regulated by Th2 immune factors.
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PMID:Mechanistic analysis of experimental food allergen-induced cutaneous reactions. 1686 16


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