UNIPROT:P15088 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P15088 (mast cell)
14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of their localization at the interface of the internal and external environment mast cells play a crucial role in the immune response and in inflammatory reactions. Effects may be mediated not only by the high-affinity IgE receptor, but also by IgG receptors. Since in rodent mast cells signal transduction via the Fc gamma receptor family has been shown, we analysed the expression of surface receptors for IgG on the human mast cell line HMC-1. It was shown by flow cytometric analysis that HMC-1 constitutively expressed the Fc gamma RII/CD32 subtype whereas Fc gamma RI/CD64 and Fc gamma RIII/CD16 were not expressed. This exclusive expression of the Fc gamma RII subtype of IgG receptor is similar to the expression pattern of basophils, although concerning cell surface molecules HMC-1 rather seem to resemble monocytes. In contrast to monocytes the expression profile on HMC-1 did not change upon stimulation with IL-4, TNF alpha, IFN gamma, PMA or salbutamol. Moreover, the mast cell-activating cytokine SCF and the calcium ionophore A23187 did not modulate the Fc gamma R profile in this study. To assess the importance of the exclusive Fc gamma RIII expression on HMC-1, we investigated whether the production of the cytokine TNF alpha is modulated via Fc gamma RII activation or if an increase in intracellular calcium could be observed. No significant modulation of TNF alpha release or of intracellular free calcium after crosslinking of Fc gamma RII by heat-aggregated IgG or by a second antibody was observed. It remains to be clarified whether this low-affinity subtype for the IgG receptor is involved in antigen-dependent sensitization of human tissue mast cells resulting in secretion of immunoregulatory cytokines. This mechanism may be important for disease states associated with circulating or tissue-bound immune complexes.
...
PMID:Human HMC-1 mast cells exclusively express the Fc gamma RII subtype of IgG receptor. 901 31

Mast cells can serve as a possible important source of cytokine production in inflamed tissue which can be regulated by stimuli different from those activating other immune system cells. To study the expression of specific genes in mast cells derived from small human colonic mucosal endoscopic biopsies, we first modified a previously reported procedure to achieve a significantly enriched mast cell fraction. Then, by using single-cell RT-PCR analysis the expression of the IgE Fc receptor (Fc epsilonRI) and c-kit mRNA was determined. It was observed that the Fc epsilonRI-positive cells also expressed c-kit. This observation provided further evidence that Fc epsilonRI-positive cells are indeed mast cells. Analysis of biopsies from 12 patients (four control and eight patients with inflammatory bowel disease (IBD)) was carried out, revealing that all of the Fc epsilonRI-positive cells expressed IL-3, while the expression of IL-4 was detected only in some of these positive cells. TNF alpha was not detected in these cells. Therefore, it would seem that most intestinal mast cells produce IL-3. Since it has been reported that IL-3 synthesis was down-regulated in steroid-treated cells, the expression pattern of IL-3 in intestinal mast cells derived from steroid-treated IBD patients was then determined. IL-3 mRNA was detected in only two out of 24 Fc epsilonRI-positive cells derived from these steroid-treated patients. These results lend strong support to the idea that the down-regulation of IL-3 in mast cells derived from steroid-treated IBD patients occurs in vivo and could be an important mechanism for immunomodulation in IBD.
...
PMID:Analysis of cytokine profile in human colonic mucosal Fc epsilonRI-positive cells by single cell PCR: inhibition of IL-3 expression in steroid-treated IBD patients. 930 51

Recent studies using mast cell-defined mice showed that the presence of mast cells was necessary for the increase in macrophage function observed after oral administration of malathion and reconstitution with bone marrow-derived mast cells restored the ability of malathion to increase macrophage function. In addition, the release of mast cell mediators (blocked by cromolyn) and histamine (action blocked by pyrilamine) was shown to be involved in the action of malathion on macrophage function. In the present study, the contribution of inflammatory mediators (i.e. arachidonic acid metabolites and tumor necrosis factor [TNF]) which may be generated by mast cells after oral administration of malathion, was examined. Controls in this study included the effects of the agent to be examined on: (1) resident peritoneal macrophages; and (2) macrophages elicited with pristane, and agent shown previously to stimulate macrophage function in the absence of mast cells. Intraperitoneal administration of indomethacin, and inhibitor of cycloxygenase, or neutralizing antibody to TNF 30 h before and 4 h after oral malathion blocked the ability of malathion to increase macrophage function, as measured by the generation of respiratory burst activity and the production of cathepsin D. On the other hand, administration of these agents to mice injected intraperitoneally with pristane did not affect the observed increase in cathepsin D production. Respiratory burst function after elicitation with pristane was slightly decreased (indomethacin) or not affected (antibody to TNF). The effect of intraperitoneal administration of nordihydroguaiaretic acid (NDGA), and inhibitor of both cycloxygenase and lipoxygenase, was also examined. Intraperitoneal administration of NDGA partially blocked the effects of oral administration of malathion on peritoneal macrophage function, but did not affect the function of resident pristane-elicited peritoneal macrophages. These data suggest that inflammatory mediators (potentially released from mast cells upon stimulation) contribute to the elevation in macrophage function observed after oral malathion administration.
...
PMID:Contributions of inflammatory mast cell mediators to alterations in macrophage function after malathion administration. 930 54

Here we show that the supernatant from activated lung mast cells induced the release of eosinophil cationic protein (ECP) from eosinophils. Lung mast cells were purified using affinity magnetic selection with monoclonal antibody (mAb) YB5.B8 to achieve a final mast cell purity of 93-99%. Eosinophils were purified by immunomagnetic negative selection (>98.0% pure). The supernatant was obtained from lung mast cells activated for 24 h with 1 microg/ml anti-IgE and 50 ng/ml stem cell factor (SCF). Human eosinophils were incubated with various concentrations of the supernatants for 4 h and ECP released was measured by RIA. Using 4 different donors' supernatant from mast cells, each donor's supernatant caused a dose-dependent release of ECP from eosinophils. The dilutant of 1:2 (v/v) of the supernatant induced 657.5 +/- 55.6 ng/10(6) eosinophils of ECP which is statistically significant (p = 0.008, n = 4) compared with the culture medium alone. Anti-interleukin (IL-5 neutralizing mAb, 10 microg/ml, and anti-tumor necrosis factor-alpha (TNF alpha) neutralizing mAb, 10 microg/ml, significantly inhibited the supernatant-induced ECP release in 79.3 +/- 9.4 and 68.2 +/- 14.1% (mean +/- SEM, n = 6, p < 0.005), respectively. Anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) neutralizing mAb, 50 microg/ml, caused 68.0 +/- 6.1% of inhibition (p = 0.002). The isotype negative control had no measurable inhibitory or stimulatory effect for the stimuli. We confirmed that mast cells produce IL-5, GM-CSF and TNF alpha in response to IgE-dependent stimulation by using RT-PCR, in situ hybridization, ELISA and immunocytochemistry. A million of lung mast cells generated 41.4 pg (7.0-273.6) (median with range) of TNF alpha, 252.6 pg (158.7-3,652) of GM-CSF and 735 pg (< 10-2,750) of IL-5 24 h after activation with SCF and anti-IgE. These findings indicate that the human mast cells may contribute to the chronicity of tissue inflammation.
...
PMID:Activation of eosinophils with cytokines produced by lung mast cells. 936 32

Assays based on reporter gene technology represent today an important tool in the pharmaceutical industry for discovering novel compound classes interfering with the activation and signaling of target cells after stimulation. Here we describe a reporter gene assay targeting mast cell activation of IgE plus antigen, established in an attempt to identify substances preventing type I allergy (allergic rhinitis, allergic conjunctivitis, allergic asthma, and acute and chronic urticaria). The assay is based on a murine mast cell line designated CPII, stimulation by IgE plus antigen, and a reporter gene construct with the TNF alpha promoter linked to luciferase as a read-out system. Via screening about 50,000 substances, compound 2 was found to inhibit the reporter gene induction in the submicromolar range in this assay. Analogues of compound 2 of the 2,3,4-trihydropyrimidino[2,1-a]isoquinoline type were synthesized starting from 2-alkyl-substituted benzonitriles via aminolysis with 1,3-diaminopropane, dimetalation of 2-substituted 2-phenyl-1,4,5,6-tetrahydropyrimidines with n- and sec-butylithium, reaction with carboxylic acid methyl esters, and finally acidic dehydration. From about 50 derivatives, compound 41 was selected as a lead structure with an IC50 of 0.2 microM and a TC50 of 2.7 microM. In a first profiling in secondary assays, it effectively interfered with the production of mediators such as TNF alpha, IL-4, IL-6, IL-13, and leukotriene synthesis as measured by the corresponding ELISAs. In addition, a passive cutaneous anaphylaxis in mice (a typical type I reaction) is inhibited to more than 90% by compound 41, when administered intradermally 90 min before challenge.
...
PMID:Inhibition of Fc epsilon RI-mediated activation of mast cells by 2,3,4-trihydropyrimidino[2,1-a]isoquinolines. 954 5

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis (HPA) and principal coordinator of the stress response. As in stress, intracerebroventricular administration of CRH suppresses the immune system indirectly, via glucocorticoid and/or sympathetic system-mediated mechanisms. Also, during inflammatory stress, the cytokines TNF alpha, IL-1, and IL-6 stimulate hypothalamic CRH and/or vasopressin secretion as a way of preventing the inflammatory reaction from overreacting. Recently, CRH receptors were described in peripheral sites of the immune system, and CRH was found to promote several immune functions in vitro. We demonstrated a direct role of CRH in the inflammatory immune process in vivo, by first studying the effect of systemic CRH immunoneutralization in an experimental model of carrageenin-induced aseptic inflammation in Spague-Dawley rats. We extended these observations to other forms of experimental inflammation, including streptococcal cell wall polysaccharide- and adjuvant-induced arthritides and peptide R16 (epitope of the interphotoreceptor retinoid-binding protein)-induced uveitis in Lewis rats. We also studied human disease states, including rheumatoid arthritis, Hashimoto thyroiditis, and ulcerative colitis. Inflamed tissues contained large amounts of IR CRH, reaching levels similar to those observed in the hypophyseal portal system. We also demonstrated the presence of CRH mRNA and CRH receptors in inflammatory cells and identified the mast cells as a major immune target for CRH. In addition to production by immune cells, the peripheral nervous system, including the postganglionic sympathetic neurons and the sensory fibers type C, appears to contribute to IR CRH production in inflammatory sites. The production of CRH from the postganglionic sympathetic neurons may be responsible for the stress-induced activation of allergic/autoimmune phenomena, such as asthma and eczema, via mast cell degranulation. Antalarmin, a novel nonpeptide CRH receptor antagonist, displaced 125I-labeled ovine CRH binding in rat pituitary, frontal cortex, and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmin significantly inhibited CRH-stimulated ACTH release and carrageenin-induced subcutaneous inflammation in rats. Thus, antalarmin and other related compounds that antagonize CRH at the level of its own receptor have therapeutic potential in some forms of inflammation directly mediated by type 1 CRH receptors and promise to enhance our understanding of the many roles of CRH in immune/inflammatory reactions.
...
PMID:Corticotropin-releasing hormone and inflammation. 962 33

Mast cell activation can be induced by multiple mechanisms, including IgE-, complement-, and stem cell factor (SCF)-mediated pathways. In addition, the interaction of mast cells with particular cell populations, such as fibroblasts, have also demonstrated increased mast cell reactivity. In these studies, we have investigated the role of fibroblast-mast cell interaction for induction of histamine release and chemokine production and the specific role of SCF during this interaction. Primary pulmonary fibroblast cell lines were grown in culture and used throughout these studies. Mast cells were grown in parallel with fibroblasts by incubation of bone marrow cells with SCF and IL-3. During mast cell-fibroblast coculture, increased histamine release could be attenuated either by separation of the cell populations using a Trans-Well setup, which did not allow cellular contact, or by specific anti-SCF Ab. In addition, a significant increase in eotaxin, a potent eosinophil-specific C-C chemokine, was also observed during fibroblast-mast cell interaction. The production of eotaxin was cell contact dependent and could be inhibited using an anti-SCF Ab or specific antisense therapy. SCF was constitutively produced from fibroblasts in its transmembrane form and could be induced by TNF. SCF-coated plates induced significant mast cell-derived eotaxin production, whereas soluble SCF induced little or no eotaxin, suggesting a necessity for receptor cross-linking for activation. These studies indicate that fibroblast-mast cell contact plays a role in exacerbation of histamine release and eotaxin production.
...
PMID:Novel role of transmembrane SCF for mast cell activation and eotaxin production in mast cell-fibroblast interactions. 963 35

The release of cytokines from cutaneous cells may be of major importance in the initiation and development of many inflammatory skin disorders. For example, tumor necrosis factor-alpha (TNF-alpha), which in healthy skin is found preformed only in mast cells, is able to induce the expression of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1). Increased expression of ICAM-1 occurs in keratinocytes in lesional skin of psoriasis and atopic dermatitis (AD) and it is considered to be an important initiator of leucocyte/keratinocyte interactions in skin inflammation. We counted the mast cells showing TNF-alpha immunoreactivity using a double-staining method in nonlesional and lesional skin sections from 12 patients with AD and 12 patients with psoriasis. The percentage of TNF-alpha+ mast cells in lesional and nonlesional AD skin was 36 +/- 22% and 21 +/- 15% (P < 0.018, paired t-test), respectively, and in psoriatic skin was 16 +/- 25% and 15 +/- 15%, respectively (P < 0.89, paired t-test). We also cultured whole skin biopsies taken from the healthy-looking skin of psoriatic and AD patients in the presence of mast cell degranulator compound 48/80, which resulted in focal expression of ICAM-1 in the epidermis. In cultured keratinocytes, both histamine and an extract of a human mast-cell line (HMC-1) induced ICAM-1 immunostaining only in occasional cells, but the combination of histamine and the HMC-1 extract resulted in intense ICAM-1 staining in numerous cells. This enhancement of ICAM-1 staining was abolished by preincubation of the HMC-1 extract with anti-TNF-alpha antibody. These results suggest that the degranulation of mast cells induces the expression of ICAM-1 in keratinocytes probably via TNF-alpha and histamine.
...
PMID:Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-alpha and their degranulation is associated with expression of ICAM-1 in the epidermis. 974 89

The mechanisms by which UV radiation is immunosuppressive are controversial, but there is growing evidence that processes of UVB-induced suppression of the immune response towards a sensitizing antigen are different if this antigen is applied to irradiated compared with non-irradiated sites. Consistent with this is our recent observation (Hart et al., J. Exp. Med. 1998. 187: 2045-2053) that the prevalence of dermal mast cells determines the extent of susceptibility of different mouse strains to UVB-induced systemic, but not local, immunosuppression. Using C57BL/6 and BALB/c mice exposed to low and high doses of UVB, respectively, in the presence of a polyclonal anti-TNF antibody, we found that TNF is directly involved as a mediator in the suppression by UVB of local immune responses. To determine whether TNF indirectly regulates UVB-induced systemic immunomodulation by altering the prevalence of dermal mast cells, dermal mast cell numbers in gene-targeted mice deficient in TNF or TNF receptors (p55/p75-/- mice) were quantified by video image analysis. A reduced dermal mast cell prevalence in these mice correlated with decreased susceptibility for systemic immunosuppression caused by UVB. We hypothesize that TNF is one molecule that controls dermal mast cell prevalence by as yet unknown mechanisms. However, it is the mediators released from mast cells upon UVB-induced degranulation, which do not include TNF, that directly signal suppressive events relevant to systemic immunosuppression.
...
PMID:TNF modulates susceptibility to UVB-induced systemic immunomodulation in mice by effects on dermal mast cell prevalence. 975 76

Previous studies have shown that mast cell granules (MCG) inhibit numerous macrophage functions including tumour cytotoxicity, superoxide and nitric oxide (NO) production, and FCgamma2a receptor-mediated phagocytosis. In this study, the effect of MCG on macrophage TNF alpha and nitric oxide synthase (iNOS) mRNA expression, and the production and fate of TNF alpha were examined. Upon activation with LPS+IFN gamma, macrophages expressed both TNF alpha and iNOS mRNA and produced both TNF alpha and NO. Co-incubation of LPS+IFN gamma-activated macrophages with MCG resulted in dose-dependent inhibition of iNOS mRNA expression. TNF alpha production in the activated macrophages was decreased by MCG, which was associated with a reduction in TNF alpha mRNA expression. MCG were also capable of degrading both macrophage-generated and recombinant TNF alpha. The direct effect of MCG on TNF alpha was partially reversed by a mixture of protease inhibitors. These results demonstrate that MCG decrease the production of NO and TNF alpha by inhibiting macrophage iNOS and TNF alpha gene expression. Furthermore, MCG post-transcriptionally alter TNF alpha levels via proteolytic degradation.
...
PMID:Effect of mast cell granules on the gene expression of nitric oxide synthase and tumour necrosis factor-alpha in macrophages. 988 71

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>