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)

Immunoglobulin (Ig)-free light chains IgLC are present in serum and their production is augmented under pathological conditions such as multiple sclerosis, rheumatoid arthritis and neurological disorders. Until now, no (patho)physiological function has been ascribed to circulating Ig light chains. Here we show that IgLCs can confer mast cell dependent hypersensitivity in mice. Antigenic stimulation results in plasma extravasation, cutaneous swelling and mast-cell degranulation. We show that IgLCs have a crucial role in development of contact sensitivity, which could be completely prevented by a novel IgLC antagonist. Although IgE and IgG(1) are central to the induction of immediate hypersensitivity reactions, our results show that IgLCs have similar activity. IgLCs may therefore be a novel factor in the humoral immune response to antigen exposure. Our findings open new avenues in investigating the pathogenesis of autoimmune diseases and their treatments.
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PMID:Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses. 1209 1

There is much evidence that angiogenesis is related to mast cells. Mast cells accumulate in many angiogenesis-dependent situations, including tumor growth, rheumatoid arthritis, ovulation, would healing, and tissue repair. Several mast cell mediators are angiogenic and regulate endothelial cell proliferation and function. Stem cell factor, vascular endothelial growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor induce chemotactic migration of mast cells to sites of neovascularization. Mast cell products such as tryptase also degrade connective tissue matrix to provide space for neovascular sprouts. Angiogenesis has been proposed as a target for anticancer therapy and for treatment of inflammatory disorders such as rheumatoid arthritis. Future studies on the cascade of angiogenic events, including mast cell-target cell interaction, and various intracellular signaling pathways are indicated to provide a new approach for the treatment of cancer and inflammatory disorders and for tissue repair.
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PMID:Mast cells and angiogenesis. 1250 Feb 62

Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, in rheumatoid arthritis, and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanisms by which mast cells migrate to various tissues under steady state conditions or during infection or inflammation. Here, we show that activation of c-Kit by its ligand, stem cell factor (SCF), cooperates with alpha4 integrin in inducing directed migration of mast cells on fibronectin. A reduction in migration and activation of a small G protein, Rac, was observed in mast cells derived from class IA phosphoinositide-3 kinase (PI-3kinase)-deficient mice in response to SCF stimulation and in mast cells expressing the dominant-negative Rac (RacN17), as well as in mast cells deficient in the hematopoietic-specific small G protein, Rac2. In addition, a PI-3kinase inhibitor inhibited alpha4- as well as SCF-induced migration in a dose-dependent fashion. In contrast, a mitogen-activated protein kinase (MAPK) inhibitor had little effect. Consistent with the pharmacologic results, abrogating the binding of the p85alpha subunit of class IA PI-3kinase to c-Kit also resulted in inhibition of SCF-induced migration on fibronectin. These genetic and biochemical data demonstrate that both c-Kit and alpha4 integrin signaling are linked to class IA PI-3kinase and Rac pathways and regulate integrin-directed (haptotactic) migration in mast cells.
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PMID:Genetic evidence for convergence of c-Kit- and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells. 1256 Feb 32

Corticotropin releasing hormone (CRH) and interleukin-6 (IL-6) are implicated in inflammatory diseases triggered by stress. Acute restraint stress increases serum IL-6 in the blood, but its source is not known. Our current study was carried out in order to determine the contribution of mast cells to stress-induced IL-6 release and to investigate skin CRH and vascular permeability in mice. W/W(v) mast cell deficient and their wild type control +/+ mice were stressed in a plexiglass restraint chamber for 60 or 120 min. Serum corticosterone and IL-6 levels were measured. Other mice were injected with (99)Tchnetium gluceptate ((99)Tc) and its extravastion, indicating vascular permeability, was determined along with CRH levels in the skin and knee joints. Acute stress increased serum IL-6 in mice, but was greatly inhibited in W/W(v) mast cell deficient mice. Vascular permeability to (99)Tc, as well as local CRH levels, were also increased by stress, but not in W/W(v) mice. Findings from our current study suggest a link between mast cells and stress-related skin and joint inflammation and may explain initial events in psoriatic and rheumatoid arthritis.
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PMID:Mast cell deficient W/W(v) mice lack stress-induced increase in serum IL-6 levels, as well as in peripheral CRH and vascular permeability, a model of rheumatoid arthritis. 1257 28

Remodeling of extracellular matrix is an important component in a variety of inflammatory disorders as well as in normal physiological processes such as wound healing and angiogenesis. Previous investigations have identified the various matrix metalloproteases, e.g., gelatinases A and B, as key players in the degradation of extracellular matrix under such conditions. Here we show that an additional enzyme, human mast cell beta-tryptase, has potent gelatin-degrading properties, indicating a potential contribution of this protease to matrix degradation. Human beta-tryptase was shown to degrade gelatin both in solution and during gelatin zymographic analysis. Further, beta-tryptase was shown to degrade partially denatured collagen type I. beta-Tryptase bound strongly to gelatin, forming high molecular weight complexes that were stable during SDS-PAGE. Mast cells store large amounts of preformed, active tryptase in their secretory granules. Considering the location of mast cells in connective tissues and the recently recognized role of mast cells in disorders in which connective tissue degradation is a key event, e.g., rheumatoid arthritis, it is thus likely that tryptase may contribute to extracellular matrix-degrading processes in vivo.
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PMID:Human mast cell beta-tryptase is a gelatinase. 1287 42

To improve our knowledge on the pathophysiology of rheumatoid arthritis (RA), we investigated gene expression patterns in synovial tissue from RA and osteoarthritis (OA) patients. DNA oligonucleotide microarray analysis was employed to identify differentially expressed genes in synovial tissue from pathologically classified tissue samples from RA (n = 20) and OA patients (n = 10). From 7131 gene sets displayed on the microarray chip, 101 genes were found to be upregulated and 300 genes to be downregulated in RA as compared with OA. Semiquantitative reverse-transcription polymerase chain reaction, Western blotting and immunohistochemistry were used to validate microarray expression levels. These experiments revealed that Cys-X-Cys receptor (CXCR)1, CXCR2 and CXCR3 mRNAs, as well as Cys-X-Cys ligand (CXCL)9 (monokine induced by IFN-gamma) and CXCL10 (IFN-gamma inducible protein 10) mRNAs, were significantly upregulated in RA as compared with OA disease. Elevated protein levels in RA synovial tissue were detected for CXCR1 and CXCR3 by Western blotting. Using immunohistochemistry, CXCR3 protein was found to be preferentially expressed on mast cells within synovial tissue from RA patients. These findings suggest that substantial expression of CXCR3 protein on mast cells within synovial tissue from RA patients plays a significant role in the pathophysiology of RA, accompanied by elevated levels of the chemokines CXCL9 and CXCL10. Mature mast cells are likely to contribute to and sustain the inflamed state in arthritic lesions (e.g. by production of inflammatory mediators such as histamine, proteinases, arachidonic acid metabolites and cytokines). Thus, the mast cell could become a potential target in therapeutic intervention.
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PMID:High CXCR3 expression in synovial mast cells associated with CXCL9 and CXCL10 expression in inflammatory synovial tissues of patients with rheumatoid arthritis. 1293 87

Plant medications have been applied to treat pains from various types of arthritis in Korea. Rheumatoid arthritis (RA) is well known to be a chronic autoimmune/inflammatory disease that leads to progressive joint damage and cartilage destruction. Accumulation and activation of mast cells have been demonstrated in rheumatoid synovial tissue. Because infiltrated mast cells and their mediators may contribute to the initiation and progression of the inflammatory process and matrix degradation of RA, we tested the inhibitory effects of "Cool-Cool" (CC, Cool-X-A), an Oriental medication, on the production and migration of major inflammatory cytokines in mast cells. CC was treated in vitro before activation of human mast cell line (HMC-1) with phorbol 12-myristate 13-acetate, and the cytotoxicity of CC was assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide assay. CC had no cytotoxic effects on HMC-1 cell viability. The inhibitory effects on cytokine production were monitored by enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction (RT-PCR). CC inhibited not only the secretion but also the expression of TNF-alpha and IL-8 in HMC-1 cells. CC also suppressed migration of mast cells induced by stem cell factor. These findings may help in understanding the mechanism of action of this herbal medication, leading to the control of mast cells in inflammatory conditions like RA.
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PMID:The Oriental medicine "Cool-Cool (Cool-X-A)" inhibits inflammatory cytokine production and migration in mast cells. 1470 95

Recent advances in our understanding of allergic and autoimmune disorders have begun to translate into novel, effective and safe medicines for these common maladies. Examples include an anti-IgE monoclonal antibody recently approved for severe asthmatics and the TNF-alpha antagonists that have demonstrated their ability to suppress rheumatoid arthritis, Crohn's disease and other chronic inflammatory processes. However, protein therapies are difficult and expensive to develop, manufacture and administer. Clearly, there is also a need for small-molecule inhibitors of novel targets that have safe and effective characteristics. Syk is an intracellular protein tyrosine kinase that was discovered 15 years ago as a key mediator of immunoreceptor signalling in a host of inflammatory cells including B cells, mast cells, macrophages and neutrophils. These immunoreceptors, including Fc receptors and the B-cell receptor, are important for both allergic diseases and antibody-mediated autoimmune diseases and thus pharmacologically interfering with Syk could conceivably treat these disorders. In addition, as Syk is positioned upstream in the cell signalling pathway, therapies targeting Syk may be more advantageous relative to drugs that inhibit a single downstream event. Syk inhibition during an allergic or asthmatic response will block three mast cell functions: the release of preformed mediators such as histamine, the production of lipid mediators such as leukotrienes and prostaglandins and the secretion of cytokines. In contrast, commonly used antihistamines or leukotriene receptor antagonists target only a single mediator of this complex cascade. Despite its expression in platelets and other non-haematopoietic cells, the role of Syk in regulating vascular homeostasis and other housekeeping functions is minimal or masked by redundant Syk-independent pathways. This suggests that targeting Syk would be an optimal approach to effectively treat a multitude of chronic inflammatory diseases without undue toxicity.
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PMID:Targeting Syk as a treatment for allergic and autoimmune disorders. 1521 16

OK205 is a traditional Korean prescription containing water-soluble chitosan, glucosamine HCl, chondroitin sulfate, and extract of herbal medicine, and has been used commercially to treat rheumatoid arthritis (RA). Because infiltrated mast cells and their mediators may contribute to the initiation and progression of the inflammatory process and matrix degradation of RA, we tested the inhibitory effects of OK205 on cytokine production in a human mast cell line (HMC-1 cells). Production of tumor necrosis factor-alpha was significantly decreased to 0.091+/-0.010 ng/ml after treatment of HMC-1 cells with OK205 100 microg/ml. The inhibition rate was about 43.57%. In addition, production of interleukin-6 in OK205 1 pg/ml-treated cells was 2.779+/-0.071 ng/ml, and the inhibition rate was about 50.22%. However, OK205 did not significantly inhibit the production of interleukin-8. These findings may help in understanding the mechanism of action of OK205, leading to control of mast cells in inflammatory conditions like RA.
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PMID:OK205 regulates production of inflammatory cytokines in HMC-1 cells. 1551 40

Traditional Korean medicine, Cheongyeolsaseuptang (CYSST) has been widely applied as a treatment of rheumatoid arthritis (RA) in Korea. However, its effect in experimental models remains unknown. Recent reports suggest that in patients with RA, synovial mast cells increase in number and show signs of activation and production of cytokines. In this study, we investigated the effect of CYSST on production of cytokines by activated human mast cell line, HMC-1. When CYSST (1mg/ml) was added, the production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 was significantly inhibited about 37, 33.6, and 48%, respectively on phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-stimulated HMC-1 cells. In addition, CYSST inhibited PMA plus A23187-induced activation of nuclear factor-kappaB. These findings may help understanding the mechanism of action of this medicine leading to control activated mast cells on inflammatory condition like RA.
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PMID:Cheongyeolsaseuptang inhibits production of TNF-alpha, IL-6 and IL-8 as well as NF-kappa B activation in human mast cells. 1565 80


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