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 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

Chemokines may control mast cell infiltrates found in many inflammatory diseases. These cells act through at least two main functions: migration and degranulation. Here we show that human recombinant monocyte chemotactic protein (MCP)-1 (10 ng/50 microliters) induces, after 4 h, an inflammatory vascular permeability and cellular extravasation reaction, determined by Evan's blue dye (1% in saline) injected into the tail vein of the rat, when injected intradermally in the rat skin. The blue color accumulating at the sites of injection provides evidence of vascular permeability and cellular extravasation. The colored areas of the skin were then enucleated and immersed in a fixative solution. Slides were prepared with sections of tissue colored with toluldine blue and analyzed under an optical microscope. A significant number of basophilic cells migrated to the injected area where MCP-1 (10 ng/50 microliters) was used compared to the control PBS treatment. Cell recruitment was slightly less than N-formyl-methionine-leucyl-phenylalanine (used at 10(-6) M/50 microliters). Electron microscopy studies confirmed the presence of basophilic granular cells where MCP-1 was intradermally injected. After preparation of a histidine decarboxylase (HDC) probe, a Northern blot analysis was determined for HDC mRNA in the enucleated tissue injected with MCP-1 (10 ng/50 microliters). Steady-state levels of HDC mRNA levels were induced after 4 h. These results were confirmed by the higher amount of histamine release, compared to the control PBS, in the enucleated tissue from the MCP-1 injection sites. Our results suggest that MCP-1 could play a significant role in diseases characterized by basophilic cell accumulation and migration to sites of tissue damage. Moreover, we show for the first time that MCP-1 is a pro-inflammatory chemokine that induces basophilic cell migration in rat skin injection sites.
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PMID:Monocyte chemotactic protein-1 is a proinflammatory chemokine in rat skin injection sites and chemoattracts basophilic granular cells. 935 62

Recent data suggest that mast cells (MC) are involved in the regulation of leukocyte accumulation in inflammatory reactions. In this study, expression of leukocyte-chemotactic peptides (chemokines) in purified human lung MC (n = 16) and a human mast cell line, HMC-1, was analyzed. Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) showed baseline expression of monocyte chemoattractant protein (MCP)-1 mRNA in unstimulated MC. Exposure of MC to recombinant stem cell factor (rhSCF, 100 ng/mL) or anti-IgE (10 microgram/mL) was followed by a substantial increase in expression of MCP-1 mRNA. Neither unstimulated nor stem cell factor (SCF )-stimulated lung MC expressed transcripts for interleukin-8 (IL-8), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, or RANTES by Northern blotting. The mast cell line HMC-1, which contains a mutated and intrinsically activated SCF-receptor, was found to express high levels of MCP-1 mRNA in a constitutive manner. Exposure of HMC-1 cells to rhSCF resulted in upregulation of MCP-1 mRNA expression, and de novo expression of MIP-1beta mRNA. The SCF-induced upregulation of MCP-1 mRNA in lung MC and HMC-1 was accompanied by an increase in immunologically detectable MCP-1 in cell supernatants (sup) (lung MC [<98%], control medium, 1 hour: 159 +/- 27 v SCF, 100 ng/mL, 1 hour: 398 +/- 46 pg/mL/10(6) cells; HMC-1: control, 1 hour: 894 +/- 116 v SCF, 1 hour: 1,536 +/- 265 pg/mL/10(6)). IgE-dependent activation was also followed by MCP-1 release from MC. MC-sup and HMC-1-sup induced chemotaxis in blood monocytes (Mo) (control: 100% +/- 12% v 2-hour-MC-sup: 463% +/- 38% v HMC-1-sup: 532% +/- 12%), and a monoclonal antibody (MoAb) to MCP-1 (but not MoAb to IL-8) inhibited Mo-chemotaxis induced by MC-sup or HMC-1-sup (39% to 55% inhibition, P < .05). In summary, our study identifies MCP-1 as the predominant CC-chemokine produced and released in human lung MC. MCP-1 may be a crucial mediator in inflammatory reactions associated with MC activation and accumulation of MCP-1-responsive leukocytes.
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PMID:The c-kit ligand stem cell factor and anti-IgE promote expression of monocyte chemoattractant protein-1 in human lung mast cells. 937 54

Chemokines probably mediate inflammation in asthma by acting on endothelial cells, alveolar cells, neutrophils, eosinophils, basophils, mast cells, monocytes, and lymphocytes, which are inhibited by corticosteroids. In 1995, we found that MCP-1 provokes mast cell aggregation and [3H]5HT-release in cultured mast cells. In another study, MCP-1 and RANTES revealed to have a potent chemoattractive effect on basophilic cells originating from the rat skin. In this inflammatory model, RANTES also attracted eosinophils and macrophages along with basophilic cells. The effect of RANTES on inducing HDC mRNA was dose dependent. MCP-1 and RANTES provoked histamine release in intradermal mast cells and prostaglandin D2 generation. These effects clearly show that RANTES and MCP-1 are mediators of acute inflammatory responses. In chronic inflammatory reactions, MCP-1 is also present as we show in a study recently published by our group. In this paper, we found that MCP-1, strongly mediates the recruitment of mononuclear cells in the granuloma formed by KMnO4. In addition, MCP-1 mediated a parasitic infection caused by Trichinella spiralis in mice. Our data strongly demonstrate that chemokines, such as RANTES and MCP-1, mediate acute inflammatory response.
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PMID:Chemokines in inflammatory states. 1047 17

Monocytes/macrophages usually make up the largest population of cells in the airways of allergic asthma patients and, as such, contribute substantially to the pathogenesis of this and other allergic diseases. In this report we address one mechanism by which monocytes can be recruited during allergic responses. We and others have shown previously that MCP-1 is important to monocyte infiltration of the tissues during allergic responses in mice and, independently, that mast cells activate fibroblasts to express type alpha1(I)-collagen during such responses. We demonstrate herein that immunologically activated, but not quiescent mouse bone-marrow-derived mast cells release mediators which in turn activate primary cultures of embryonic dermal fibroblasts for high-level secretion of monocyte chemoattractant activities. We identify the CC chemokine MCP-1 as a major component of this activity. Anti-MCP-1 antibodies neutralized approximately 80% of the monocyte chemoattractant activities secreted by such mast-cell-activated fibroblasts. Furthermore, our data implicate mast cell TGFbeta and TNFalpha in this process. Depletion of TGFbeta, TNFalpha, or both TGFbeta and TNFalpha from the mediator pool secreted by mast cells activated via the FcepsilonRI reduced the mast-cell-driven fibroblast MCP-1 response by 80+/-15, 56+/-11, or 82+/-5%, respectively. These data thus further delineate a mechanism by which fibroblasts are recruited into and participate in the mast cell-leukocyte cytokine cascades that orchestrate allergic responses.
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PMID:TGFbeta1 and TNFalpha secreted by mast cells stimulated via the FcepsilonRI activate fibroblasts for high-level production of monocyte chemoattractant protein-1 (MCP-1). 1080 72

Zymosan-induced peritonitis was investigated in mast cell-deficient WBB6F1 mice and in Balb/c mice pretreated with mast cell stabilizer (cromolyn) or antagonists of histamine receptors (mepyramine, triprolidine, cimetidine, or ranitidine). The inherited mast cell deficiency in W/Wv knockouts of WBB6F1 mice impaired significantly the level of histamine and plasma exudation (measured 30 min after stimulation) as well as the influx of exudatory leukocytes, accumulation of plasma and exudate chemoattractants, and the release of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) measured at 6 h of inflammation. All of those factors were fully restored after selective intraperitoneal reconstitution of W/Wv mice with bone marrow-derived mast cells from their control +/+ counterparts. Cromolyn pretreatment of Balb/c mice reduced exclusively the early plasma exudation and histamine influx. Blocking of histamine receptors inhibited not only the early plasma exudation but also temporarily diminished primary leukocyte influx and levels of MCP-1 and IL-1beta. In conclusion, mast cells play an important role in the initiation of zymosan-induced peritonitis and modulate its further course.
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PMID:Role of mast cells in zymosan-induced peritoneal inflammation in Balb/c and mast cell-deficient WBB6F1 mice. 1120 65

1. Chemokine expression and function was monitored in an experimental model of granulomatous tissue formation after injection of croton oil in complete Freund's adjuvant (CO/CFA) into mouse dorsal air-pouches up to 28 days. 2. In the first week, mast cell degranulation and leukocyte influx (mononuclear cell, MNC, and polymorphonuclear cell, PMN) were associated with CXCR2, KC and macrophage inflammatory protein (MIP)-2 mRNA expression, as determined by TaqMan reverse transcriptase-polymerase chain reaction. KC ( approximately 400 pg x mg protein(-1), n=12) and MIP-2 (approximately 800 pg x mg protein(-1), n=12) proteins peaked at day 7, together with myeloperoxidase (MPO) activity. Highest MIP-1alpha (>1 ng x mg protein(-1), n=12) levels were measured at day 3. 3. After day 7, a gradual increase in CCR2 and CCR5 mRNA, monocyte chemoattractant protein (MCP)-1 mRNA and protein expression was measured. MCP-1 protein peaked at day 21 (approximately 150 pg x mg protein(-1), n=12) and was predominantly expressed by mast cells. A gradual increase in N-acetyl-beta-D-glucosaminidase (NAG) activity (maximal at 28 days) was also measured. 4. An antiserum against MIP-1alpha did not modify the inflammatory response measured at day 7 (except for a 50% reduction in MIP-1alpha levels), but provoked a significant increase in MPO, NAG and MCP-1 levels as measured at day 21 (n=6, P<0.05). An antiserum to MCP-1 reduced NAG activity at day 21 but increased MPO activity values (n=8, P<0.05). 5. In conclusion, we have shown that CO/CFA initiates a complex inflammatory reaction in which initial expression of MIP-1alpha serves a protective role whereas delayed expression of MCP-1 seems to have a genuine pro-inflammatory role.
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PMID:Analysis of the temporal expression of chemokines and chemokine receptors during experimental granulomatous inflammation: role and expression of MIP-1alpha and MCP-1. 1170 36

We review evidence that Stem Cell Factor (SCF) plays an important role in the pathophysiology of asthma. SCF is produced by a wide variety of cells present in asthmatic lung, including mast cells and eosinophils. Its receptor, c-kit, is broadly expressed on mature mast cells and eosinophils. SCF promotes recruitment of mast cell progenitors into tissues, as well as their local maturation and activation. It also promotes eosinophil survival, maturation and functional activation. SCF enhances IgE-dependent release of mediators from mast cells, including histamine, leukotrienes, cytokines (TNF-alpha, IL-5, GM-CSF) and chemokines (RANTES/CCL5, MCP-1/CCL2, TARC/CCL17 e MDC/CCL22); it is required for IL-4 production in mast cells. SCF, acting in concert with IgE, also upregulates the expression and function of CC chemokine receptors in mast cells. Structural and resident airway cells express increased levels of SCF in the bronchus of asthmatic patients. In a murine model of asthma, allergen exposure increased production of SCF by epithelial cells and alveolar macrophages, which was transient and paralleled by histamine release. SCF induced long-lived airway hyperreactivity, which was prevented by local neutralization of SCF, as well as by inhibitors of the production or activity of cysteinyl-leukotrienes. Together, these observations suggest that SCF has an important role in asthma.
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PMID:Stem cell factor: a hemopoietic cytokine with important targets in asthma. 1456 Nov 50

We examined the effect of two nitrogenous diphenyl ether pesticides, nitrofen (NIP) and chlornitrofen (CNP), on mast cell activation. RBL-2H3 (rat basophilic leukemia) cells were exposed to NIP or CNP for 30 min to investigate their effect on degranulation, and for 3 h to investigate their effect on cytokine production and gene expression. NIP and CNP increased IgE receptor-mediated beta-hexosaminidase release, MCP-1 release, and TNF-alpha release in a dose-dependent manner. The increasing effect of CNP on their release was greater than that of NIP. In the gene expression experiment, 30 microg/ml CNP significantly upregulated Egr-1, MCP-1 and GADD45a gene expression. These results suggest that at higher concentrations (more than 30 microg/ml) the nitrogenous diphenyl ether pesticides had both a degranulation-enhancing effect and proinflammatory cytokine-production enhancing effect through the expression of some transcription factors in RBL-2H3 cells.
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PMID:Effect of two nitrogenous diphenyl ether pesticides on mast cell activation. 1511 79

Eosinophil-mediated diseases, such as allergic asthma, eosinophilic fasciitis, and certain hypersensitivity pulmonary disorders, are characterized by eosinophil infiltration and tissue injury. Mast cells and T cells often colocalize to these areas. Recent data suggest that mast cells can contribute to eosinophil-mediated inflammatory responses. Activation of mast cells can occur by antigen and immunoglobulin E (IgE) via the high-affinity receptor (FcepsilonRI) for IgE. The liberation of proteases, leukotrienes, lipid mediators, and histamine can contribute to tissue inflammation and allow recruitment of eosinophils to tissue. In addition, the synthesis and expression of a plethora of cytokines and chemokines (such as granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-1 [IL-1], IL-3, IL-5, tumor necrosis factor-alpha [TNF-alpha], and the chemokines IL-8, regulated upon activation normal T cell expressed and secreted [RANTES], monocyte chemotactic protein-1 [MCP-1], and eotaxin) by mast cells can influence eosinophil biology. Stem cell factor (SCF)-c-kit, cytokine-cytokine receptor, and chemokine-chemokine receptor (CCR3) interactions leading to nuclear factor kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK) expression, and other signaling pathways can modulate eosinophil function. Eosinophil hematopoiesis, activation, survival, and elaboration of mediators can all be regulated thus by mast cells in tissue. Moreover, because eosinophils can secrete SCF, eosinophils can regulate mast cell function in a paracrine manner. This two-way interaction between eosinophils and mast cells can pave the way for chronic inflammatory responses in a variety of human diseases. This review summarizes this pivotal interaction between human mast cells and eosinophils.
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PMID:The role of human mast cell-derived cytokines in eosinophil biology. 1515 10


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