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)

Hapten-specific and mast cell-dependent biphasic cutaneous reactions were induced by intravenous application of anti DNP-IgE antibodies and a subsequent skin test. These reactions were also demonstrated in SCID mice, which indicates that T cell-mediated immunity might not be involved in these IgE-mediated cutaneous reactions. Simultaneous application of anti histaminics did not suppress these reactions significantly, while several immunomodulators, such as azelastine, FK506, and prednisolone, significantly inhibited both early and late phase reactions except for the failure of FK506 to inhibit the early reaction. Anti-VCAM-1 antibody and anti-tumor necrosis factor-alpha (TNF alpha) antibody but not anti-IL 5 antibody showed similar suppressive effects on both early and late phase reactions. Mast cell and inflammatory cells other than T cells are thought to play an important role in these IgE-induced biphasic reactions. TNF alpha and/or VCAM-1 are required for tissue accumulation of inflammatory cells in this system.
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PMID:Effect of mast cell modulators on IgE-mediated murine biphasic cutaneous reactions. 863 25

Aggregation of the high-affinity Fc receptors for immunoglobulin E (IgE) (FcepsilonRI) on the surface of mast cells initiates intracellular signal transduction pathways including the tyrosine phosphorylation of cellular proteins, phosphoinositide hydrolysis, an increase in intracellular calcium, and protein kinase C activation. These signals are believed to be involved in the exocytic release of inflammatory mediators such as vasoactive amines, cytokines, and lipid metabolites. However, the downstream consequences of these early activation events are not well defined. One exception is the activation of the extracellular signal-regulated kinases/mitogen-activated protein kinases. One member of the mitogen-activated protein kinase superfamily, designated c-Jun amino-terminal kinase (JNK), has been recently identified. JNK is activated following dual phosphorylation at a Thr-Pro-Tyr motif in response to diverse stimuli including tumor necrosis factor-alpha, heat shock, or ultraviolet irradiation. We found that JNK was strongly activated by antigen cross-linking in a mouse mast cell line passively sensitized with ovalbumin-specific IgE. Anti-mouse IgE antibody also activated JNK. MEK kinase 1 (MEKK1) which activates the JNK activator, JNK kinase (JNKK), was similarly activated by antigen stimulation. JNK but not p42(erk2) activation induced by antigen was significantly inhibited in the presence of wortmannin, a known inhibitor of phosphatidylinositol 3-kinase. These results indicate that in response to the aggregation of FcepsilonRI on mast cells, phosphatidylinositol 3-kinase activation is involved in the stimulation of the MEKK1, JNKK, JNK pathway.
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PMID:Aggregation of the FcepsilonRI on mast cells stimulates c-Jun amino-terminal kinase activity. A response inhibited by wortmannin. 866 3

The participation of tumor necrosis factor-alpha (TNF-alpha) in a IgE-mediated cutaneous reaction in WBB6F1-W/Wv (W/Wv), mast cell deficient, mice and the effect of prednisolone on this cutaneous reaction were investigated. Mice were passively sensitized by an intravenous injection of monoclonal anti-dinitrophenol (DNP) IgE, and their ears challenged epicutaneously with dinitrofluorobenzene 24 h later. The cutaneous reaction estimated by ear thickness reached a peak 48-72 h after the antigen challenge. A monoclonal anti-tumor necrosis factor (TNF)-alpha antibody inhibited the IgE-mediated cutaneous reaction. An increase of TNF-alpha mRNA was demonstrated 4 h after the application of antigen by the reverse transcriptase-polymerase chain reaction. The injection of recombinant murine TNF-alpha induced a cutaneous reaction which peaked at 24 h in nonsensitized mice. Prednisolone at doses of 3 to 10 mg/kg clearly inhibited the IgE-mediated cutaneous reaction, however, it did not affect the expression of TNF-alpha-mRNA. Prednisolone at doses of 1 to 10 mg/kg clearly inhibited the TNF-alpha-induced cutaneous reaction. These results suggest that TNF-alpha plays a role in the IgE-mediated cutaneous reaction in W/Wv mice and that prednisolone inhibits the cutaneous reaction at least in part by inhibiting the action of TNF-alpha.
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PMID:TNF-alpha participates in an IgE-mediated cutaneous reaction in mast cell deficient, WBB6F1-W/Wv mice. 868 93

Lipopolysaccharide (LPS) concentrations in the portal vein after intraperitoneal (i.p.) injection were slightly higher than those in the arteries. The tumor necrosis factor (TNF alpha) levels in arterial serum were higher after i.p. injection than after i.v. injection and rose to a peak at 90 min after some delay. Infusion of LPS into the portal vein increased the TNF alpha levels in the arterial serum. Pretreatment with indomethacin further increased the arterial levels of TNF alpha after portal infusion, but did not after them after i.p. injection, because of the reduction by indomethacin of LPS absorption after i.p. Injection of LPS. TNF alpha was also generated in the peritoneal cavity after i.p. injection of LPS. The TNF alpha concentrations in the arterial serum and in the peritoneal cavity were accelerated by mast cell degradation. In conclusion, TNF alpha was generated mainly in the liver, but also in the peritoneal cavity, after i.p. injection of LPS, and was negatively regulated by prostaglandins.
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PMID:Release site of TNF alpha after intravenous and intraperitoneal injection of LPS from Escherichia coli in rats. 869 85

Mast cells are pleiotropic bone marrow-derived cells found in mucosal and connective tissues and in close apposition to neurons, where they play important roles in tissue inflammation and in neuroimmune interactions. Connective tissue mast cells, with which intracranial mast cells share many characteristics, contain cytokines that can cause inflammation. Here, we report that myelin basic protein, a major suspected immunogen in multiple sclerosis, as well as an antigenic stimulus, provokes mast cells to trigger a delayed cytotoxicity for neurons in mixed neuron-gila cultures from hippocampus. Neurotoxicity required a prolonged period (12 h) of mast cell incubation, and appeared to depend largely on elaboration of the free radical nitric oxide by astrocytes. Activation of astrocytes was mediated, in part, by mast cell-secreted tumor necrosis factor-alpha. Myelin basic protein and 17 beta-estradiol had a synergistic action on the induction of mast cell-associated neuronal injury. The cognate mast cell line RBL-2H3, when subjected to an antigenic stimulus, released tumor necrosis factor-alpha which, together with exogenous interleukin-1 beta (or interferon-gamma), induced astroglia to produce neurotoxic quantities of nitric oxide. A small but significant proportion of mast cell-derived neurotoxicity under the above conditions occurred independently of glial nitric oxide synthase induction. Further, palmitoylethanolamide, which has been reported to reduce mast cell activation by a local autacoid mechanism, decreased neuron loss resulting from mast cell stimulation in the mixed cultures but not that caused by direct cytokine induction of astrocytic nitric oxide synthase. These results support the notion that brain mast cells could participate in the pathophysiology of chronic neurodegenerative and inflammatory diseases of the nervous system, and suggest that down-modulation of mast cell activation in such conditions could be of therapeutic benefit.
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PMID:Mast cell activation causes delayed neurodegeneration in mixed hippocampal cultures via the nitric oxide pathway. 876 79

Chronic proliferative dermatitis is a spontaneous mutation in C57BL/Ka mice (cpdm/cpdm), showing alopecia, epithelial hyperproliferation, infiltration by eosinophils and macrophages, and vascular dilatation. To further elucidate its pathogenesis, organs of 1-, 2-, 3-, 4-, 5-, and 6-week-old cpdm/cpdm mice were examined. At 4 weeks, the epidermal thickness was increased, whereas already at 3 weeks, the bromodeoxyuridine incorporation was increased in the basal keratinocytes. However, already at the age of 1 week, skin, lungs, and lymph nodes were infiltrated by eosinophils although no macroscopic lesions were present. Compared with control animals, 6-week-old cpdm/cpdm mice had decreased serum IgE levels and increased numbers of mast cells. From the age of 1 week these mast cells became increasingly IgE positive. In contrast, the mast cells of the control animals remained IgE negative. Mast cells of control and cpdm/cpdm mice were interleukin-4 and tumor necrosis factor-alpha positive. A likely explanation for the tissue infiltration of eosinophils could be the release of interleukin-4 and tumor necrosis factor-alpha from activated mast cells. Tumor necrosis factor-alpha may lead to the expression of E-selectin on endothelial cells, facilitating interleukin-4-mediated eosinophil transendothelial migration. Although various pathogenetic aspects of the cpdm/cpdm mouse need further elucidation, this model can be a tool to study eosinophil infiltration, leukocyte-endothelial cell interactions, and mast cell proliferation. Furthermore, the cpdm/cpdm mouse can be used to study chronic inflammatory skin disease because of the severe epidermal proliferation.
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PMID:Pathogenesis of skin lesions in mice with chronic proliferative dermatitis (cpdm/cpdm). 877 48

Nerve growth factor (NGF) promotes mast cell survival in vitro (Horigome, K., Bullock, E. D., and Johnson, E. M., Jr. (1994) J. Biol. Chem. 269, 2695-2702). NGF survival promotion is cell density-dependent, and conditioned medium experiments have shown that NGF increases the production of an autocrine mast cell survival activity. Cytokines are potential candidates for autocrine survival factors. In rat peritoneal mast cells (RPMC), NGF caused an increase in the messenger RNAs for interleukin (IL)-3, IL-4, IL-10, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor. This induction was NGF dose-dependent, was blocked by NGF-neutralizing antibodies, and was not observed in the non-mast peritoneal cell population. The immunosuppressive agent, cyclosporin A, blocked both cytokine induction and NGF-activated survival promotion but not survival promotion activated by IL-3 or stem cell factor, suggesting that NGF enhanced RPMC survival by increasing cytokine production. We also examine the effects of NGF on the expression levels of some members of the bcl-2 family and the interleukin-1beta-converting enzyme-like cysteine protease families. NGF markedly increased bcl-2 expression but had little or no effect on the other genes studied. The induction of bcl-2 mRNA by NGF was not blocked by cyclosporin A. These data suggest that induced cytokine gene expression but not increased expression of bcl-2 mediates NGF-survival promotion in RPMC.
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PMID:Nerve growth factor induces the expression of certain cytokine genes and bcl-2 in mast cells. Potential role in survival promotion. 891 Mar 34

If cell numbers, activation state, or mediators, for example, can be correlated with some clinical measure of disease severity, a major effector role in the disease may be postulated. Mast cells, along with eosinophils and lymphocytes, are present in increased numbers in the airways of patients with asthma. Mast cell mediators are also increased in persons with allergies, with the concentrations of histamine, tryptase, and prostaglandin D2 being proportional to the degree of airway obstruction and bronchial hyperresponsiveness. Increased numbers of activated must cells and eosinophils (but not T cells or macrophages) were also found in bronchoalveolar lavage fluid in children. The mast cell is also known to release a range of cytokines (e.g., tumor necrosis factor-alpha and IL-4) that have various important functions, including upregulation of the endothelial adhesion molecules that are responsible for eosinophil recruitment from the microvascular circulation into the airways and subsequent activation. Mast cell staining for secreted IL-4 was found to be proportional to the infiltration of eosinophils and lower airway symptoms in patients with seasonal asthma, which is compatible with the concept that mast cells alone can sustain a continuing allergic inflammatory response. The mast cell proteases chymase and tryptase are also important for eosinophil recruitment and activation and for increasing mucus secretion and microvascular permeability. The evidence that the human mast cell is capable of releasing proteases and cytokines that have the capacity to initiate and maintain a chronic inflammatory response provides a mechanism whereby the clinical efficacy of nedocromil sodium in patients with chronic mild to moderate asthma can be explained.
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PMID:The immunopharmacology of mild asthma. 893 71

We previously showed that interleukin-3 (IL-3) alone is not sufficient, although it is essential for murine mucosal-type mast cell development and that prostaglandin E (PGE) and interferon-gamma (IFN-gamma) are critical for survival or differentiation of mast cell precursors. We also confirmed that IL-4 is a key inhibitor for mast cell precursors despite being a growth factor of mast cells. In the present work, mouse spleen cells were cultured with recombinant (r) IL-1 beta, rIL-5, rIL-6, rIL-9, granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), tumor transforming growth factor-beta (TGF-beta), or tumor necrosis factor-alpha (TNF-alpha) in the presence of endogenous IL-3. After 12 days of culture, mast cell development was induced by rIL-6 and rTNF-alpha, rIL-1 beta, rIL-5, rGM-CSF, rTGF-beta and even the mast cell growth factors, rIL-9 and rSCF, failed to induce mast cell development. However, unlike IL-9 and SCF, IL-6 and TNF-alpha did not promote the growth of mast cells already developed. Macrophage may be one of the responsive cells of IL-6 and TNF-alpha in the cultures, because removal of macrophages greatly reduced the mast cell development induced by the cytokines. The actions of TNF-alpha and IL-6 were inhibited by indomethacin, an inhibitor for prostaglandin synthesis, and by neutralizing anti-IFN-gamma and anti-IL-3 antibodies. rIL-4, when added at the start of the culture, also inhibited mast cell development induced by rIL-6 and rTNF-alpha. Nevertheless, neutralizing anti-IL-6 and anti-TNF-alpha antibodies did not suppress mast cell development induced by PGE and IFN-gamma. TNF-alpha and IL-6 enhanced IFN-gamma production, but suppressed IL-4 production in the cultures. Mast cell numbers induced were inversely and directly proportional to IL-4 and IFN-gamma levels, respectively. These results indicate that inflammatory mediators as triggers are important for mast cell development although they are not the mast cell growth factors.
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PMID:Tumor necrosis factor-alpha- and interleukin-6-triggered mast cell development from mouse spleen cells. 900 55

Pathologic fibroblast proliferation or tissue fibrosis develops in certain chronic allergic diseases and in a wide array of other inflammatory disorders in which mast cell activation is also a prominent feature. In this study we investigated a number of potential mechanisms by which IgE-dependent activation of mouse mast cells might influence the proliferation of mouse fibroblasts in vitro. We found that supernatants from in vitro-derived mast cells that had been activated by IgE and specific antigen (but not those from quiescent mast cells) promoted the proliferation of mouse embryonic skin or 3T3 fibroblasts, and we showed that this effect was detectable in the absence of fetal calf serum. We analyzed the kinetics with which the fibroblast-proliferative activity was secreted from bone marrow-derived cultured mast cells and found that it was released both rapidly (i.e., in 30 minutes or less) and for a more prolonged period (i.e., for more than 2 hours) after IgE-dependent mast cell activation. We then measured the levels at which the mast cells produce a number of cytokines that are known to affect fibroblasts (IL-1, IL-6, transforming growth factor-beta 1 [TGF-beta 1], and tumor necrosis factor-alpha [TNF-alpha]) and assessed their relative effects, as recombinant cytokines, on fibroblast proliferation. Our mast cells secreted high levels of TGF-beta 1 and TNF-alpha, intermediate amounts of IL-6, and low levels of IL-1. We titrated the fibroproliferative effects of each of these cytokines and determined that at a dose of 50 pg/ml their rank order of activity was TGF-beta 1 > TNF-alpha > IL-1 > IL-6, with all but IL-6 having significant effects. The ability of supernatants from activated bone marrow-derived cultured mast cells to promote fibroblast proliferation was partially diminished by absorption with neutralizing antibodies against either TNF-alpha or TGF-beta 1, and absorption of the supernatants with a combination of antibodies against TNF-alpha and TGF-beta 1 reduced their ability to induce fibroblast proliferation by approximately 50% (p < or = 0.001, n = 5). These findings show that IgE-dependent activation of mouse mast cells can result in the release of mediators that promote fibroblast proliferation in the absence of any other cell type and suggest that mast cell-derived TNF-alpha and TGF-beta 1 contribute substantially to this effect. They also suggest that these cytokines exert their effects through synergistic interactions with other mast cell mediators.
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PMID:Promotion of mouse fibroblast proliferation by IgE-dependent activation of mouse mast cells: role for mast cell tumor necrosis factor-alpha and transforming growth factor-beta 1. 900 19


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