Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of drugs for the treatment of allergic disease is an important subject in human health. Stimulation of mast cells starts the process of degranulation resulting in releasing of mediators, such as histamine. In this report, we investigated the effect of aqueous extract of Dracocephalum argunense Fisch. (Labiatae) (DAAE) on the mast cell-mediated allergic response and studied its possible mechanisms of action, focusing on the histamine release and pro-inflammatory cytokine secretion in mast cells. DAAE inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. In addition, DAAE attenuated IgE-mediated skin allergic reaction. DAAE dose-dependently reduced IgE-induced histamine release from mast cells. The level of cAMP was transiently increased by treatment of DAAE. DAAE specifically blocked the phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-induced p38 mitogen-activated protein kinase (MAPK) activation. DAAE decreased the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 in mast cells. Our findings provide evidence that DAAE inhibits mast cell derived allergic reactions, and involvement of cAMP for histamine release and p38 MAPK for pro-inflammatory cytokine secretion in these effects.
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PMID:Action of Dracocephalum argunense on mast cell-mediated allergy model. 1650 52

Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin (Ig)E-bound FcepsilonRI. Diacylglycerol kinase (DGK)zeta is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGKzeta-/- mice have enhanced in vivo T cell function. Here, we demonstrate that these mice have diminished in vivo mast cell function, as revealed by impaired local anaphylactic responses. Concordantly, DGKzeta-/- bone marrow-derived mast cells (BMMCs) demonstrate impaired degranulation after Fc epsilonRI cross-linking, associated with diminished phospholipase Cgamma activity, calcium flux, and protein kinase C-betaII membrane recruitment. In contrast, Ras-Erk signals and interleukin-6 production are enhanced, both during IgE sensitization and after antigen cross-linking of Fc epsilonRI. Our data demonstrate dissociation between cytokine production and degranulation in mast cells and reveal the importance of DGK activity during IgE sensitization for proper attenuation of Fc epsilonRI signals.
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PMID:Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-deficient mast cells. 1671 14

1. Mast cells cultured from human peripheral blood have been used as a cell model for functional studies of human mast cells, particularly human lung mast cells. However, the beta-adrenoceptor subtype expressed by these cultured cells has not been identified. The aim of the present study was to characterize pharmacologically the beta-adrenoceptors involved in the suppression of IgE-mediated release of mediators, including histamine, prostaglandin (PG) D2 and leukotriene (LT) C4 from cultured mast cells. 2. Mast cells were cultured from mast cell progenitors isolated from peripheral blood in the presence of 200 ng/mL stem cell factor and 50 ng/mL interleukin-6. Mast cells were sensitized with human myeloma IgE, treated with beta-adrenoceptor agonists or antagonist and then challenged with anti-human IgE. The release of histamine, PGD2 and LTC4 from mast cells was determined. 3. Both isoprenaline and salbutamol inhibited anti-IgE-induced release of histamine, PGD2 and LTC4 from cultured mast cells in a dose-dependent manner. Isoprenaline was a more potent inhibitor than salbutamol. The pD2 values for the inhibition of the release of histamine, PGD2 and LTC4 were 7.37 +/- 0.12, 8.38 +/- 0.23, 8.85 +/- 0.23, respectively, for isoprenaline and 6.96 +/- 0.12, 7.65 +/- 0.36, 7.91 +/- 0.64, respectively, for salbutamol. The selective beta3-adrenoceptor agonist BRL-37344 failed to affect anti-IgE-induced histamine release from cultured mast cells. 4. The selective beta2-adrenoceptor antagonist ICI 118 551 (108 mol/L) strongly reversed the concentration-dependent suppression of histamine release by isoprenaline and salbutamol; however, the selective beta1-adrenoceptor antagonist atenolol (106 mol/L) did not have any effect. 5. These results indicate that both isoprenaline and salbutamol act at beta2-adrenoceptors to suppress IgE-mediated mediator release from cultured human mast cells.
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PMID:Beta-adrenoceptor-mediated inhibition of mediator release from human peripheral blood-derived mast cells. 1689 50

The immediate-type allergic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. The discovery of drugs for the treatment of immediate-type allergic diseases is a very important subject in human health. In this study, we investigated the effect of Artemisia iwayomogi (AIAE) on mast cell-mediated allergic reaction and inflammatory cytokine secretion. AIAE inhibited compound 48/80-induced systemic reactions in mice. AIAE decreased the passive cutaneous anaphylaxis (PCA) reaction activated by antidinitrophenyl (anti-DNP) IgE antibody. AIAE dose-dependently reduced histamine release from rat peritoneal mast cells activated by compound 48/80 or anti-DNP IgE. Furthermore, AIAE attenuated the phorbol 12-myristate 13-acetate plus calcium ionophore A23187-stimulated tumor necrosis factor-alpha and interleukin-6 secretion in human mast cells. These results provide evidence that AIAE may be beneficial in the treatment of allergic diseases.
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PMID:Artemisia iwayomogi inhibits immediate-type allergic reaction and inflammatory cytokine secretion. 1699 91

The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is controversially discussed in ischemia/reperfusion damage of the heart. Purpose of this study was to elucidate cellular sources of TNFalpha and parameters which possibly influence its release in the heart following ischemia. Isolated hearts of mice were subjected to 15 min of global ischemia and 90 min of reperfusion. We employed hearts of various mice knock-out strains (interleukin-6(-/-), matrix metalloprotease-7(-/-), mast-cell deficient WBB6F1-Kit(W)/Kit(W-v), TNF-R1(-/-)) and wildtype mice, the latter perfused without and with infusion of cycloheximide or TNFalpha-cleaving-enzyme inhibitor (TAPI-2). Normoxic control hearts showed basal release of TNFalpha during the whole experiment. Immunohistology identified cardiac mast cells, macrophages and endothelial cells as main sources. TNFalpha release was stimulated during postischemic reperfusion, occurring in a two-peak pattern: directly after ischemia (0-10 min) and again after 60-90 min. The first peak mainly reflects tissue washout of TNFalpha accumulated during ischemia. The second, protracted peak arose continuously from the basal level and was abolished by protein synthesis inhibitor cycloheximide. Both properties are characteristic for de novo synthesis of TNFalpha, e.g., in cardiac muscle cells. However, immunohistological staining for TNFalpha failed in cardiomyocytes after 90 min of reperfusion. In contrast to hearts of TNF-R1(-/-) and Kit(W/W-v)-mice, those of IL-6(-/-) and MMP-7(-/-) mice lacked the late TNFalpha peak. TAPI did not suppress release of TNFalpha. While autostimulation via TNF-R1 also does not seem obligatory and mast cell can be ignored as source of the second peak, IL-6 may support de novo synthesis of TNFalpha. Additionally, TNFalpha release may essentially involve cleavage of membrane bound TNFalpha by MMP-7.
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PMID:Insights from knock-out models concerning postischemic release of TNFalpha from isolated mouse hearts. 1710 Nov 48

Findings obtained using animal models have often failed to reflect the processes involved in human disease. Moreover, human cultured cells do not necessarily function as their actual tissue counterparts. Therefore, there is great demand for sources of human progenitor cells that may be directed to acquire specific tissue characteristics and be available in sufficient quantities to carry out functional and pharmacological studies. Acase in point is the mast cell, well known for its involvement in allergic reactions, but also implicated in inflammatory diseases. Mast cells can be activated by allergens, anaphylatoxins, immunoglobulin-free light chains, superantigens, neuropeptides, and cytokines, leading to selective release of mediators. These could be involved in many inflammatory diseases, such as asthma and atopic dermatitis, which worsen by stress, through activation by local release of corticotropin-releasing hormone or related peptides. Umbilical cord blood and cord matrix-derived mast cell progenitors can be separated magnetically and grown in the presence of stem cell factor, interleukin-6, interleukin-4, and other cytokines to yield distinct mast cell populations. The recent use of live cell array, with its ability to study such interactions rapidly at the single-cell level, provides unique new opportunities for fast output screening of mast cell triggers and inhibitors.
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PMID:Human umbilical cord blood-derived mast cells: a unique model for the study of neuro-immuno-endocrine interactions. 1723 53

Myocardial ischemia-reperfusion (IR) injury complicates all forms of coronary artery revascularization. Circulating interleukin-6 (IL-6) has been implicated in cell death following a variety of stimuli. Macrophages, platelets, neutrophils and the endothelium have been shown to release IL-6 after IR injury. Cardiac mast cells have been implicated in IR; however, their involvement has never been quantified. In this randomized, prospective study, we compared cardiac tissue susceptibility and serum IL-6 changes between mast cell deficient (W/Wv) mice and their normal littermates (+/+). Twenty-eight male W/Wv mice (n=14) and their +/+ littermates (n=14) were anaesthetized with 2.5% isoflurane. The left coronary artery (LCA) was ligated for 30 minutes or a sham procedure was performed. After 6 hours of reperfusion, the animals were sacrificed. The muscle viability was assessed on fresh whole-mount slices by nitroblue tetrazolium (NBT) histochemical assay and serum IL-6 concentrations measured by ELISA. Cardiac muscle viability was significantly higher in W/Wv mice than the +/+ mice. Serum IL-6 levels were higher in the +/+ sham mice (465 +/- 32 pg/ml, n=6) than the W/Wv mice (185 +/- 31 pg/ml, n=6), p < 0.001. The IL-6 levels increased significantly after reperfusion only in the +/+ mice (698 +/- 41 pg/ml, n=8, p = 0.001), while it remained similar in the W/Wv mice (202 +/- 48 pg/ml, n=8, p = 0.783). These results show that the absence of mast cells reduces the myocardial damage associated with IR injury. Furthermore, there is an attenuation in the inflammatory response, as measured by serum IL-6 levels, following this local insult. This finding entertains the prospect of developing prophylactic therapy--targeting selective inhibition of cardiac mast cell activation, in clinical situations involving medical or surgical myocardial revascularization.
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PMID:Mast cell deficient W/Wv mice have lower serum IL-6 and less cardiac tissue necrosis than their normal littermates following myocardial ischemia-reperfusion. 1734 29

Mast cells are well known for their involvement in allergic and anaphylactic reactions, during which immunoglobulin E (IgE) receptor (Fc epsilon RI) aggregation leads to exocytosis of the content of secretory granules (1000 nm), commonly known as degranulation, and secretion of multiple mediators. Recent findings implicate mast cells also in inflammatory diseases, such as multiple sclerosis, where mast cells appear to be intact by light microscopy. Mast cells can be activated by bacterial or viral antigens, cytokines, growth factors, and hormones, leading to differential release of distinct mediators without degranulation. This process appears to involve de novo synthesis of mediators, such as interleukin-6 and vascular endothelial growth factor, with release through secretory vesicles (50 nm), similar to those in synaptic transmission. Moreover, the signal transduction steps necessary for this process appear to be largely distinct from those known in Fc epsilon RI-dependent degranulation. How these differential mast cell responses are controlled is still unresolved. No clinically available pharmacological agents can inhibit either degranulation or mast cell mediator release. Understanding this process could help develop mast cell inhibitors of selective mediator release with novel therapeutic applications.
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PMID:Differential release of mast cell mediators and the pathogenesis of inflammation. 1749 52

During neuronal-induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcepsilonRI-independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti-IgE and compound 48/80. Primary cultured mast cells, generated from CD34(+) progenitors in the presence of stem cell factor and interleukin-6 (IL-6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti-IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein-1, inducible protein-10, monokine induced by interferon-gamma (MIG), RANTES (regulated on activation, normal, T-cell expressed, and secreted) and IL-8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL-3 and granulocyte-macrophage colony-stimulating factor, but not IL-4, interferon-gamma or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti-IgE up-regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G-protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases.
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PMID:Neuropeptides activate human mast cell degranulation and chemokine production. 1792 33

In this study, we investigated the effect of the methanol extract of fruits of Vitis amurensis Rupr. (Vitaceae; MEVA) on the mast cell-mediated allergy model and studied the possible mechanism of action. Mast cell-mediated allergic disease is involved in many diseases, such as asthma and sinusitis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. MEVA inhibited compound 48/80-induced systemic reactions and serum histamine release in a dose-dependent manner in mice. MEVA decreased immunoglobulin E (IgE)-mediated local allergic reactions, passive cutaneous anaphylaxis. MEVA dose-dependently reduced histamine release from mast cells activated by compound 48/80 or IgE. The inhibitory effect of MEVA on histamine release was mediated by the modulation of intracellular calcium. In addition, MEVA attenuated the phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated secretion of tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-8 in human mast cells. The inhibitory effect of MEVA on these proinflammatory cytokines was p38 mitogen-activated protein kinase and nuclear factor-kappaB (NF-kappaB) dependent. Our findings provide evidence that MEVA inhibits mast cell-derived, immediate-type allergic reactions and involvement of proinflammatory cytokines, p38 MAPK, and NF-kappaB in these effects.
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PMID:Antiallergic effects of Vitis amurensis on mast cell-mediated allergy model. 1822 74


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