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)

The mast cell is one of the major effector cells in inflammatory reactions and can be found in most tissues throughout the body. During inflammation, an increase in the number of mast cells can be seen, e.g., in the intraepithelial cell layer after a provoked allergic reaction. Such accumulation probably requires directed migration of mature mast cells or their precursors. To study the migration of human mast cells we used as a model the human mast cell line, HMC-1, and stem cell factor-dependent (also referred to as mast cell growth factor or Kit ligand) cord blood-derived mast cells. The results show that stem cell factor is a potent chemotactic factor for human mast cells in vitro. The chemotactic response to SCF was found to be dose dependent, reaching a maximum at 50 ng/ml. The activity of SCF could be blocked by anti-SCF Abs. We also tested the effect of different intercrines, i.e., IL-8, MIP-1 alpha, MIP-1 beta, RANTES, and MCAF (also referred to as monocyte chemotactic protein 1), on human mast cell migration. Only RANTES was chemotactic for in vitro-developed mast cells. None of the tested intercrines induced migration of HMC-1 cells. For migration, the mast cells were dependent on binding to an extracellular matrix protein. Thus, coating of the filters with fibronectin was required, whereas collagen or laminin did not promote migration. Adhesion of HMC-1 cells to fibronectin could also be shown in an adhesion assay. In addition, expression of receptors for fibronectin could be detected on the surface of the mast cells. These results show that SCF is not only a growth and differentiation factor for human mast cells in vitro but also a potent chemoattractant for such cells.
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PMID:Stem cell factor is a chemotactic factor for human mast cells. 752 4

We have determined that several chemokines induce mast cell migration in vitro. This directed migration is dependent on the presence of particular extracellular matrix proteins and the activation status of the cells. Mast cell haptotactic responses were observed in response to various chemokines on vitronectin-, laminin-, and fibronectin-coated filters. Unstimulated mast cells were chemoattracted only by monocyte chemotactic protein-1 and RANTES on vitronectin-coated and, to a lesser extent, laminin-coated filters, whereas IgE-activated mast cells migrated in response to monocyte chemotactic protein-1, regulated on activation normal T expressed and secreted, platelet factor-4, and macrophage inflammatory protein-1 alpha on all three matrix proteins. No significant migration was observed on collagen type IV-coated or uncoated filters. Mast cell migration in response to chemokines on extracellular matrices and its enhancement by IgE-dependent activation provide a mechanism by which cells may be drawn to sites of inflammation. Chemokine-induced mast cell recruitment may be particularly relevant in host defense responses to parasitic infections, allergic reactions, Jones-Mote reactions, and in wound healing.
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PMID:Bone marrow-derived murine mast cells migrate, but do not degranulate, in response to chemokines. 753 69

Chemokines are proinflammatory peptides regulating the functions of various hematopoietic cells. We have analyzed the effects of seven recombinant human (rh) chemokines (MCAF, RANTES, MIP-1 alpha, MIP-1 beta, IL-8, GRO, and IP-10) on the growth and function of human basophils and mast cells. We found that MCAF, but not RANTES, MIP-1 alpha, MIP-1 beta, IL-8, GRO, or IP-10, causes direct and dose-dependent histamine release from basophils (MCAF, 5 micrograms/ml: 26.9 +/- 3.4%; other chemokines: < 5% of total histamine). An increased (2.1 to 3.5-fold) response to MCAF was obtained when basophils were preincubated with rh interleukin-3 (100 units/ml). Moreover, IL-3-primed basophils became responsive to physiologic concentrations (< 1 microgram/ml) of MCAF, IL-8, and RANTES. None of the chemokines tested was able to induce histamine secretion in mast cells obtained from lung (n = 2), skin (n = 1), uterus (n = 3), or tonsils (n = 3), even when cells had been preincubated with the mast cell agonist SCF. The chemokines also failed to modulate the expression of activation antigens (CD11b/C3biR, CD25/IL-2R beta, CD63, IL-3R alpha, CD117/c-kit) on the mast cell line HMC-1 or the basophil cell line KU-812 and were unable to induce differentiation of basophils or mast cells in culture. Together, our results show that basophils respond to rhIL-8, rhMCAF, and rhRANTES and that, unlike human basophils, human mast cells are unresponsive to recombinant chemokines.
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PMID:Differential response of human basophils and mast cells to recombinant chemokines. 754 Dec 56

Chemokines are considered important mediators of various inflammatory processes. In human basophils, different CC chemokines are known to stimulate release of histamine and generation of leukotriene (LT)C4. In the present study, we have evaluated the effect of RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemotactic protein (MCP)-1, MCP-2, MCP-3, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta on mast cell activation. Whereas all these CC chemokines caused dose-dependent release of histamine from basophils in mixed human leukocyte suspensions, none of them was able to induce release of histamine as well as tryptase or prostaglandin (PG)D2 from human skin mast cells, nor did priming with these substances enhance IgE-mediated mediator release. In addition, all chemokines failed to promote changes in the cytosolic free calcium level in the human mast cell line HMC-1. These results add further evidence for the differences between human mast cells and basophils regarding cytokine-dependent activation.
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PMID:Effect of CC chemokines on mediator release from human skin mast cells and basophils. 758 Feb 86

Mast cells are an important source of a number of lymphokines and chemokines primarily those released after challenge with the allergic trigger IgE and Ag. However, the mechanisms of lymphokine and chemokine gene activation in this cell type, as opposed to the mechanisms of activation in T cells, are poorly understood. As a model system, we addressed this issue in mast cells by using the recently cloned chemokine MARC gene, which belongs to the RANTES/sis gene family. After allergic stimulation, MARC induction is pronounced and mast cell specific. Northern blot analysis, in combination with two inhibitors, actinomycin D and cycloheximide, resulted in the formation of our initial hypothesis, which was that both transcriptional and post-transcriptional regulation are involved after stimulation through the Fc epsilon R. We performed a detailed promoter analysis of the cloned MARC gene by using transient assays of transfected reporter gene constructs. Thereby, two potential promoter regions were identified as being crucial for transcriptional stimulation. Additional fine mapping of the proximal element and subsequent electrophoretic mobility shift assays, combined with competitions of known transcription factor binding sites, identified one of the transcription factors in stimulated mast cells as an AP3 or AP3-like binding activity.
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PMID:A transcription factor with AP3-like binding specificity mediates gene regulation after an allergic triggering with IgE and Ag in mouse mast cells. 798 69

Allergic airway inflammation is characterized by peribronchial eosinophil accumulation with the submucosa surrounding the airway. The initial induction of immunoglobulin E (IgE)-mediated mast cell degranulation, up-regulation of adhesion molecules, and the production of inflammatory and chemotactic cytokines, leading to the infiltration of specific leukocyte subsets, is orchestrated in a sequential manner. The activation and degranulation of local mast cell populations is an immediate airway response mediated both by antigen-specific, surface bound IgE and by cytokine-induced activational pathways. Subsequently the infiltration and activation of effector leukocytes (neutrophils and eosinophils) mediated by the persistent activation of allergen-specific T cells leads to pathological manifestations within the lung and airway. The development of appropriate animal models to dissect the critical mechanisms involved in antigen-induced airway pathology is crucial for the development of efficacious therapies. We have utilized a model of allergic airway inflammation induced by intratracheal challenge with parasite (Schistosoma mansoni) egg antigen in presensitized mice. This model has proven useful in the assessment of eosinophil recruitment and has identified key cytokines involved in leukocyte elicitation. These cytokines include interleukin-4 and elicitation. These cytokines include interleukin-4 and tumor necrosis factor, which appear to act as early response mediators, as well as C-C chemokines, macrophage inflammatory protein-1a, and RANTES, which act directly on eosinophil recruitment. In addition, we have found that both C-X-C and C-C chemokines are expressed in pulmonary-derived mast cells, suggesting an important contribution to leukocyte responses in the allergic airway.
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PMID:Activation and regulation of chemokines in allergic airway inflammation. 855 61

The proteolytic cleavage product of complement component 3, (C3a), is like C4a and C5a, is a potent anaphylatoxin and induces the production of inflammatory mediators in phagocytes. Notably, mast cells respond to C3a with the release of vasoactive substances, including histamine. We have examined the function and receptor binding of C3a in a human leukemic mast cell line, HMC-1. Similar to chemoattractant agonists in leukocytes, C3a induced rapid cytosolic free calcium concentration increases in HMC-1 cells. EGTA did not diminish this response, indicating that mobilizable Ca2+ was from intracellular stores. Receptors of C3a in HMC-1 cells couple in part to Bordetella pertussis toxin-sensitive G-proteins and, therefore, appear to belong to the family of serpentine receptors that require G-proteins for signal transduction. HMC-1 cells express two types of C3a receptors, C3aR1 and C3aR2, that were shown to bind 125I-C3a with high-(Kd1 = 2.1-4.8 nM) or low-affinity (Kd2 = 30-150 nM), and both receptors are expressed at high level: 3 x 10(5)-6 x 10(5) C3aR1/cell and 5 x 10(5)-2.3 x 10(6) C3aR2/cell. Results from cross-linking experiments with 125I-C3a fully agree with the presence of two different classes of C3a receptors in HMC-1 cells. Two membrane proteins with apparent molecular masses of 54-61 kDa (p57) and 86-107 kDa (p97) could be covalently modified with 125I-C3a, and this cross-linking was inhibited with an excess of unlabeled C3a. Many of the known agonists for leukocytes including 13 chemokines (IL-8, NAP-2, GRO alpha, ENA-78, IP10, PF4, MCP-1, 2 and 3, RANTES, MIP-1 alpha, MIP-1 beta and I309), three neuropeptides (neuropeptide Y, somatostatin and calcitonin), as well as C5a, did not activate HMC-1 cells, indicating that C3a is one of a few protein ligands for which this cell line expresses specific receptors. The apparent selectivity for C3a and the abundant expression of C3a receptors make the HMC-1 cell line an excellent choice for the cloning of the receptor genes.
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PMID:Expression of high- and low-affinity receptors for C3a on the human mast cell line, HMC-1. 862 64

Cell priming and stimulation of different cytokines (which include chemokines and growth factors) are typical features of human basophils. Recently, it has been shown that the macrophage chemotactic protein-1 (MCP-1), RANTES and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are potent direct secretagogues for human basophils and that interleukin-3 (IL-3), IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are priming factors for subsequent potentiation of mediator release from basophils induced by different stimuli. This observation may be clinically important for the activation and recruitment of inflammatory cells in different immune responses of the skin (e.g. late-phase reactions). The aim of the present study was to investigate whether cytokines and chemokines are also capable of priming or stimulating isolated human skin mast cells (SMC). SMC were either stimulated directly with the cytokines alone or preincubated with these factors for 10 min before being activated with suboptimal concentrations of anti-IgE, A23187 or substance P. IL-3, IL-5, GM-CSF, platelet factor-4 (PF-4), IL-8, MCP-1 and MIP-1 alpha (each at concentrations of 1 ng/ml to 1 microgram/ml, log steps) did not significantly modulate histamine release from SMC induced by the three different secretagogues. RANTES exhibited a weak but significant potentiating effect on IgE-mediated activation. Stem cell factor (SCF) as a positive control was able to prime mast cell histamine release strongly. In addition, PF-4, MCP-1, RANTES and MIP-1 alpha were incapable of inducing direct histamine release from SMC. In experiments with isolated human peripheral basophils, however, we observed potent Fc epsilon RI-mediated priming effects evoked through IL-3, IL-5 and GM-CSF. We conclude that SMC derived from healthy donors are not targets of (immuno)modulatory factors that prime or stimulate basophils.
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PMID:Effects of basophil-priming and stimulating cytokines on histamine release from isolated human skin mast cells. 884 26

T lymphocytes have been implicated in controlling the recruitment of eosinophils into the lung in murine models of allergic asthma. The mechanism by which T cells assist in the recruitment of eosinophils to the lung in these models is not completely understood. We hypothesized that eosinophil-active chemokines might be regulated by antigen (Ag)-induced T cell activation in vivo and thereby mediate T cell-dependent eosinophil recruitment. To test this hypothesis, we examined the effect of an anti-CD3 mAb on Ag-induced pulmonary eosinophilia and correlated this with the expression of three eosinophil-active chemokines: eotaxin, macrophage inflammatory protein (MIP)-1 alpha, and RANTES. We found that Ag-induced pulmonary eosinophilia was associated with the induction of eotaxin and MIP-1 alpha, but not RANTES mRNA. Prechallenge treatment with anti-CD3 mAb inhibited eotaxin, but not MIP-1 alpha and RANTES mRNA induction, and significantly reduced eosinophil accumulation in the lung. In addition, Ag-specific antibody responses and mast cell degranulation after Ag challenge in sensitized mice were not affected by T cell elimination, and were not sufficient to induce the expression of eotaxin and cause pulmonary eosinophilia. These findings suggest that eotaxin is one of the molecular links between Ag-specific T cell activation and the recruitment of eosinophils into the airways.
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PMID:T cell-dependent regulation of eotaxin in antigen-induced pulmonary eosinophila. 887 17

Allergic rhinitis is an increasing problem for which new and exciting therapies are being developed. These can be understood through an appreciation of the newer concepts of pathogenesis of allergic rhinitis. Allergen induces Th2 lymphocyte proliferation in persons with allergies with the release of their characteristic combination of cytokines including IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13. These substances promote IgE and mast cell production. Mucosal mast cells that produce IL-4, IL-5, IL-6, and tryptase proliferate in the allergic epithelium. Inflammatory mediators and cytokines upregulate endothelial cell adhesion markers, such as vascular cell adhesion molecule-1. Chemoattractants, including eotaxin, IL-5, and RANTES, lead to characteristic infiltration by eosinophils, basophils, Th2 lymphocytes, and mast cells in chronic allergic rhinitis. As our understanding of the basic pathophysiologic features of allergic rhinitis continues to increase, the development of new diagnostic and treatment strategies may allow more effective modulation of the immune system, the atopic disease process, and the associated morbidity.
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PMID:Pathogenesis of allergic rhinitis. 904 69


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