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)

We have previously shown that mast cells enhance eosinophil survival and activation. In this study we further characterized mast cell activity toward eosinophils. Sonicate of both rat peritoneal mast cells and the human mast cell line 1 (HMC-1) induced a concentration-dependent IL-6 and IL-8 release from human peripheral blood eosinophils (ELISA). HMC-1-induced IL-8 release was significantly reduced by the tryptase inhibitors GW-45 and GW-58 (90 and 87%, respectively, at an optimal concentration) but not by anti-stem cell factor, anti-TNF-alpha, or anti-IFN-gamma neutralizing Abs or by the antihistamine drugs pyrilamine and cimetidine. In a manner similar to HMC-1, human recombinant tryptase induced the expression of mRNA for IL-8 (RT-PCR) and caused IL-8 release from the eosinophils. Addition of cycloheximide, actinomycin D, dexamethasone, PD 98059, curcumin, or SB 202190 completely inhibited the tryptase-induced IL-6 and IL-8 release. In contrast, cyclosporin A had no effect on tryptase-induced IL-8 release. Tryptase caused phosphorylation of extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases 1 and 2, and p38 (Western blot). Tryptase also induced the translocation of c-Jun from the cytosol to the nucleus (confocal microscopy) and enhanced AP-1 binding activity to the DNA (EMSA). Eosinophils were found to express proteinase-activated receptor 2 (FACS). When eosinophils were incubated with tryptase in the presence of anti-proteinase-activated receptor 2 antagonist Abs a significant decrease in the IL-6 and IL-8 release occurred. In summary, we have demonstrated that the preformed mast cell mediator tryptase induces cytokine production and release in human peripheral blood eosinophils by the mitogen-activated protein kinase/AP-1 pathway.
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PMID:Tryptase activates the mitogen-activated protein kinase/activator protein-1 pathway in human peripheral blood eosinophils, causing cytokine production and release. 1219 39

The generation of cytokines, particularly TNF-alpha, by mast cells is crucial for the initiation of the allergic response. A key transcription factor involved in the synthesis of TNF-alpha is NF-kappaB. Using a mAb specific for the activated form of NF-kappaB, immunocytochemistry, confocal microscopy, and gel shift assays have been used in conjunction to localize this transcription factor to human lung mast cells and to study its activation. Activation of mast cells with stem cell factor (10 ng/ml) and anti-IgE (1 micro g/ml) induced maximal activation of NF-kappaB at 4 and 2 h, respectively. In contrast, with TNF-alpha (5 ng/ml) maximal activation occurred within 15 min. Parallel falls in IkappaB were demonstrated. Confocal microscopy demonstrated the localization of the activated form of NF-kappaB to the nuclei of activated mast cells. NF-kappaB activation was verified using a gel shift assay. A supershift assay showed mast cell NF-kappaB to be composed primarily of p50 with smaller amounts of p65. No interaction with Abs for Rel-A, c-Rel, Rel-B, and p52 was seen. Immunocytochemistry and ELISAs showed TNF-alpha to be stored within mast cells and released into the extracellular environment following activation. The possible participation of TNF-alpha generated by mast cells in NF-kappaB activation by anti-IgE was investigated using a blocking Ab for TNF-alpha. The blocking Ab reduced NF-kappaB activation by anti-IgE by >50%, suggesting that the release of preformed mast cell-associated TNF-alpha acts as a positive autocrine feedback signal to augment NF-kappaB activation and production of further cytokine, including GM-CSF and IL-8.
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PMID:NF-kappa B and TNF-alpha: a positive autocrine loop in human lung mast cells? 1239 Dec 48

Human mast cells are often found perivascularly and at mucosal sites and may play crucial roles in the inflammatory response. Recent studies have suggested a prominent role for mast cells in host defense. In this study, we analyzed the effects of a common airway pathogen, Moraxella catarrhalis and a commensal bacterium, Neiserria cinerea, on activation of human mast cells. Human mast cell leukemia cells (HMC-1) were activated with either phorbol myristate acetate (PMA) and calcium ionophore or with varying concentrations of heat-killed suspensions of bacteria. Supernatants were assayed for the cytokines interleukin-4 (IL-4), granulocyte macrophage colony stimulating factor (GM-CSF), IL-6, IL-8, IL-13 and monocyte chemotactic protein-1 (MCP-1). Nuclear proteins were isolated and assayed by electrophoretic mobility shift assay (EMSA) for nuclear factor kappaB (NF-kappaB) nuclear binding activity. In some experiments, NF-kappaB inhibitor, Bay-11 was added to determine functional significance. Both M. catarrhalis and N. cinerea induced mast cell activation and selective secretion of two key inflammatory cytokines, IL-6 and MCP-1. This was accompanied by NF-kappaB activation. Neither spun bacterial supernatants nor bacterial lipopolysaccharide induced cytokine secretion, suggesting need for direct bacterial contact with mast cells. Scanning electron microscopy revealed active aggregation of bacteria over mast cell surfaces. The NF-kappaB inhibitor, Bay-11, inhibited expression of MCP-1. These findings suggest the possibility of direct interactions between human mast cells and common bacteria and provide evidence for a novel role for human mast cells in innate immunity.
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PMID:Moraxella catarrhalis induces mast cell activation and nuclear factor kappa B-dependent cytokine synthesis. 1245 64

Orf virus causes pustular skin lesions (orf) in sheep, goats and humans. The virus encodes an interleukin-10 (orfvIL-10) that is identical in amino acid composition to ovine IL-10 (ovIL-10) over the C terminal two-thirds of the polypeptide, but not in the N terminal third. The immuno-suppressive and immuno-stimulatory activities of orfvIL-10 and ovIL-10 were compared. Both orfvIL-10 and ovIL-10 inhibited TNF-alpha and IL-8 cytokine production from stimulated ovine macrophages and keratinocytes and IFN-gamma and GM-CSF production from peripheral blood lymphocytes. OrfvIL-10 and ovIL-10 co-stimulated both ovine and murine mast cell proliferation in conjunction with IL-3 (ovine) or IL-4 (murine). Isoleucine at position 87 (Ile(87)) of the mature human IL-10 (huIL-10) has been reported as essential for the immuno-stimulatory activity of huIL-10. In spite of the differences in amino acids within the N-terminal third of orfvIL-10 compared with ovIL-10 and substitution of Ile(87) with Ala(87) in ovIL-10, these variants of ovIL-10 and orfvIL-10 all co-stimulated mast cell proliferation and inhibited macrophage IL-8 production. As ovIL-10 and orfvIL-10 have a similar structure to huIL-10 and conserved receptor-binding residues, it was concluded that Ile(87) is not essential for IL-10 immuno-stimulatory activity. Finally, ovine keratinocytes do not express ovIL-10. This might explain why orf virus has evolved a viral IL-10.
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PMID:A comparison of the anti-inflammatory and immuno-stimulatory activities of orf virus and ovine interleukin-10. 1245 84

A new pimarane-type diterpene compound, acanthokoreoic acid A together with three known compounds, acanthoic acid, acanthol, and sumogaside were isolated from a CH(2)Cl(2) fraction of Acanthopanax koreanum by repeated column chromatography and reversed phase preparative HPLC. Acanthoic acid was isolated in high yields and showed potent inhibitory activity on the IL-8 secretion of the TNF-alpha-stimulated human colon adenocarcinoma cell line HT-29 and on the TNF-alpha secretion of the trypsin-stimulated human leukemic mast cell line HMC-1.
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PMID:Inhibitory effect of TNF-alpha and IL-8 secretion by pimarane-type diterpenoids from Acanthopanax koreanum. 1273 67

Chitosan is widely used to treat patients with hypoxia-induced diseases such as ischemia, neuronal death, cerebral stroke, and cerebral infarction. Using the ELISA method, we examined the effect of high molecular weight water-soluble chitosan (WSC) on inflammatory cytokine production in the desferrioxamine (DFX, known to mimic hypoxia)-stimulated human mast cell line HMC-1. DFX significantly increased interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha production compared with the control in a time-dependent manner (p<0.05), but did not affect IL-1alpha production and mRNA expression. The increase in IL-6, IL-8, and TNF-alpha levels was significantly inhibited by WSC in a dose-dependent manner with IC(50) values of 0.77, 0.88, and 2.5 microg/ml, respectively. The maximal inhibition rate of IL-6, IL-8, and TNF-alpha production by WSC was 64+/-9.7%, 80+/-9.4% and 54+/-4.5%, respectively. In addition, WSC inhibited DFX-induced activation of nuclear factor (NF)-kappaB. In conclusion, these results suggest that WSC is an inhibitor of NF-kappaB under hypoxic conditions, which might explain its beneficial effect in the treatment of hypoxia-induced inflammatory diseases.
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PMID:Inhibitory effect of high molecular weight water-soluble chitosan on hypoxia-induced inflammatory cytokine production. 1273 19

Stress induces CRH secretion that activates hypothalamic-pituitary-adrenal axis and is also abortogenic. In addition to hypothalamus, CRH and its analog urocortin (Ucn) are also secreted locally outside the brain where they activate mast cells leading to inflammation; however, the level of CRH and Ucn or mast cell mediators has not been examined in products of conception (POC). CRH and Ucn were measured by enzyme immunoassay, tryptase by fluoroenzyme immunoassay, and IL-8 by ELISA in POC of 7-9 wk gestation from Caucasian women; they were divided into group I with elective abortions (n = 4), group II with one spontaneous abortion (n = 12), and group III with at least two spontaneous abortions (n = 7). CRH, Ucn, tryptase, and IL-8 levels were higher (P < 0.05) in group III (8683 +/- 1201 pg/g, 7961 +/- 1499 pg/g, 1553 +/- 572 ng/g, and 8317 +/- 1874 pg/g, respectively) than group II (2561 +/- 314 pg/g, 2349 +/- 394 pg/g, 403 +/- 97 ng/g, and 3199 +/- 449 pg/g, respectively) and group I (163 +/- 162 pg/g, 328 +/- 327 pg/g, 72 +/- 31 ng/g, and 3681 +/- 931 pg/g, respectively). Immunostaining of POC showed significantly more tryptase in group III women. High POC levels of CRH and Ucn under stress in habitual spontaneous abortions may activate uterine mast cells to secrete abortogenic tryptase and IL-8.
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PMID:High levels of intrauterine corticotropin-releasing hormone, urocortin, tryptase, and interleukin-8 in spontaneous abortions. 1460 8

We investigated the expression and the role of hypoxia-inducible factor 1alpha (HIF-1alpha) on the desferrioxamine (DFX)-induced cytokine production in human mast cells, HMC-1 cells. HIF-1alpha mRNA was constitutively expressed in mast cell lines including the P815, RBL-2H3, and HMC-1. DFX (100 microM) resulted in a great increase in protein levels of HIF-1alpha in HMC-1 cells, but it did not affect HIF-1alpha mRNA expression. Iron (HIF-1 inhibitor) inhibited increase of HIF-1alpha and NF-kappaB protein levels. Pyrriolidine-dithiocarbamate (PDTC, NF-kappaB inhibitor) inhibited increase of NF-kappaB protein levels, but it slightly increased HIF-1alpha protein levels. In addition, DFX significantly increased the production of IL-6, IL-8, and TNF-alpha in HMC-1 (P<0.05). These increased cytokine levels were significantly inhibited by treatment of iron or PDTC in a dose-dependent manner (P<0.05). We demonstrated the regulatory effects of HIF-1alpha on the DFX-induced proinflammatory cytokine production in human mast cells for the first time. These data indicate that inflammatory cytokines seem to be under HIF-1alpha or NF-kappaB transcriptional regulation in the hypoxic conditions on mast cells.
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PMID:Expression of proinflammatory cytokines via HIF-1alpha and NF-kappaB activation on desferrioxamine-stimulated HMC-1 cells. 1282 Nov 13

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

Mast cells act as central effector and regulatory cells in many inflammatory disorders, including T helper 1 (T(H1))-mediated inflammations such as autoimmunity and T(H2)-mediated inflammations such as allergy and parasite infections. One characteristic for mast cell-mediated inflammations is the accumulation of mast cells in the inflamed tissue. The factors regulating mast cell recruitment in these inflammations are still not fully characterized. We have investigated the potency of T(H1)- and T(H2)-secreted cytokines to mediate mast cell migration. Supernatants from six different T(H1) and T(H2) clones were tested for mast cell-chemotactic activity using the human mast cell line (HMC-1) as a responder cell. All six clones produced factors that induced mast cell migration. Using blocking antibodies to a broad range of cytokines, we found that anti-tumour necrosis factor-alpha (anti-TNF-alpha) reduced the migration of mast cells to supernatants from T(H1) clones. In contrast, the main mast cell chemoattractants secreted by T(H2) clones were found to be interleukin-4 (IL-4) and IL-8. The potency of these cytokines to act as mast cell chemoattractants was confirmed by using recombinant IL-4, IL-8 and TNF-alpha. Our results suggest that TNF-alpha can be involved in the recruitment of mast cells in T(H1)-mediated inflammations, whereas IL-4 and IL-8 might play a similar role in T(H2)-mediated inflammations.
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PMID:Regulation of mast cell migration by T and T cytokines: identification of tumour necrosis factor-alpha and interleukin-4 as mast cell chemotaxins. 1503 May 77


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