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)

The photochemotherapeutic value of topical 8-methoxypsoralen (8-MOP) plus UVA irradiation has been well recognized. The phototoxicity associated with psoralen plus UVA (PUVA) therapy is hallmarked by an increase in vascular permeability (iVP), the accumulation of polymorphonuclear leukocytes (aPMN) and erythema formation in situ. Rose bengal (RB) plus UVA-VIS light (320-700 nm) produces a similar acute inflammatory response, but without immediate or delayed erythema and perceptible edema. This study describes some of the parameters involved in inflammatory reactions evoked by PUVA and the results are compared with RB-induced phototoxic reactions. The rates of iVP and aPMN with a 3 h pulse were quantified using 125I-albumin and 51Cr-labelled PMNs respectively. The erythemal response was graded visually. 8-MOP cream was applied topically, while RB was injected intradermally in rabbit skin before UVA-VIS (9.4 J cm-2) irradiation. The data show that there is no significant difference in the rates of iVP, aPMN and erythema formation between normal skin sites and mast cell-depleted skin sites when challenged with 8-MOP plus light. These results suggest that in situ mast cells do not play a significant role in 8-MOP-photoinduced acute cutaneous inflammatory reactions, in contrast with RB-photoinduced reactions. The iVP and aPMN responses are minimal or absent in sites subjected to repeated exposure to 8-MOP plus light for three or more consecutive days, suggesting the establishment of a desensitized/unresponsive state. Moreover, 8-MOP-photo-desensitized sites do not produce iVP and aPMN of the same magnitude as the normal (naive) skin sites when challenged with RB plus light. Similarly, RB-photo-desensitized sites do not produce iVP and aPMN of the same magnitude as the native skin sites when challenged with 8-MOP plus light. The desensitization and cross-desensitization of skin sites to 8-MOP- or RB-photoinduced reactions suggest that there is either direct attack on the target cell(s), thereby removing the ability to express adhesion molecules, such as endothelial leukocyte adhesion molecule 1 (ELAM-1) or intercellular adhesion molecule 1 (ICAM-1), involved in the accumulation of inflammatory cells, or downregulation of the secretion/release of putative agent(s), such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), responsible for the initiation and progression of cutaneous inflammations.
 ...
PMID:Comparative studies on the tolerance to photoinduced cutaneous inflammatory reactions by psoralen and rose bengal. 908 68

Substance P (SP) has been shown to mediate granulocyte infiltration into the mouse skin by inducing mast cell degranulation. In this study, using a variety of specific inhibitors, we investigated the cascade of events involved in the response of neutrophils and eosinophils to SP. The prostaglandin inhibitor, indomethacin, had little effect on SP-induced leukocyte migration. In contrast, pretreatment with the leukotriene (LT) synthesis inhibitor, A-64077, completely blocked neutrophil but not eosinophil migration in response to SP. Participation of tumor necrosis factor alpha (TNF-alpha) and LFA-1/ICAM-1 interaction was confirmed by inhibition of SP-induced leukocyte migration by pretreatment of mice with monoclonal antibodies to TNF-alpha, LFA-1, and ICAM-1. Moreover, alteration in leukocyte migration by indomethacin was found to depend on the concentration of TNF-alpha used. Indomethacin did not alter the number of leukocytes induced by low concentrations of TNF-alpha (0.1 ng), but reduced the number of cells stimulated with high TNF-alpha concentrations (1.0 ng). These results support the concept that SP modulates in vivo neuroinflammatory responses, as measured by granulocyte migration, initiating a cascade of events that includes LT production, TNF-alpha secretion, and engagement of LFA-1 and ICAM-1.
 ...
PMID:Involvement of leukotrienes, TNF-alpha, and the LFA-1/ICAM-1 interaction in substance P-induced granulocyte infiltration. 910 31

Mast cells are constituent cells of vascular tissue and their numbers are increased in atherosclerotic vessels. To gain insight into the role of mast cells in vascular inflammation, the effect of mast cell granules (MCG) on endothelial cell production of interleukin-6 (IL-6) was examined. Human umbilical vein endothelial cells (HUVEC) were cultured with lipopolysaccharide (LPS) in the presence or absence of rat peritoneal MCG and IL-6 production was assayed by enzyme-linked immunosorbent assay. The interaction of MCG with HUVEC in culture was examined by electron microscopy (EM). The EM studies revealed that MCG are internalized by HUVEC and appear intact even after 24 h in culture. Unactivated HUVEC produced little or no IL-6 either in the presence or absence of MCG. Treatment of HUVEC with LPS stimulated IL-6 production in a dose- and time-dependent fashion. Addition of MCG to LPS-activated HUVEC-resulted in the potentiation of IL-6 production at all LPS doses. MCG-induced enhancement of IL-6 production was evident even at a mast cell-to-endothelial cell ratio of 1:32. The enhancement of IL-6 production by MCG was also seen when tumor necrosis factor alpha was used as an activator. Although potentiation was evident when MCG were added 6 h before or after LPS stimulation, the maximum effect was noted when MCG and LPS were added simultaneously. MCG-mediated enhancement of IL-6 production was abrogated by pretreating MCG with protease inhibitors. Although MCG proteases potentiate IL-6 production by HUVEC, they do not degrade secreted IL-6. These results demonstrate that MCG interact with endothelial cells and modulate the production of an important inflammatory cytokine.
 ...
PMID:Mast cell granules potentiate endotoxin-induced interleukin-6 production by endothelial cells. 926 35

Engagement of the mast cell high-affinity receptor for immunoglobulin E (IgE), FcepsilonRI, induces tyrosine phosphorylation of Syk, a non-receptor tyrosine kinase, that has been demonstrated as critical for degranulation. Herein we describe a synthetic compound, ER-27319, as a potent and selective inhibitor of antigen or anti-IgE-mediated degranulation of rodent and human mast cells. ER-27319 affected neither Lyn kinase activity nor the antigen-induced phosphorylation of the FcepsilonRI but did effectively inhibit the tyrosine phosphorylation of Syk and thus its activity. As a consequence, tyrosine phosphorylation of phospholipase C-gamma1, generation of inositol phosphates, release of arachidonic acid, and secretion of histamine and tumor necrosis factor alpha were also inhibited. ER-27319 did not inhibit the anti-CD3-induced tyrosine phosphorylation of phospholipase C-gamma1 in Jurkat T cells, demonstrating a specificity for Syk-induced signals. In contrast the tyrosine phosphorylation and activation of Syk, induced by in vitro incubation with the phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) of FcepsilonRI gamma subunit or by antigen activation of RBL-2H3 cells, was specifically inhibited by ER-27319. However, when ER-27319 was added to immunoprecipitated Syk, derived from activated cells, no effect was seen on Syk activity. ER-27319 did not inhibit the tyrosine phosphorylation of Syk induced by activation in the presence of Igbeta ITAM or the anti-IgM-induced phosphorylation of Syk in human peripheral B cells. Therefore, ER-27319 selectively interferes with the FcepsilonRI gamma phospho-ITAM activation of Syk in vitro and in intact cells. These results confirm the importance of Syk in FcepsilonRI-mediated responses in mast cells and demonstrate the mast cell selectivity and therapeutic potential of ER-27319 in the treatment of allergic disease.
 ...
PMID:ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of fcepsilon receptor I-mediated activation of Syk. 935 85

Activated mast cells reside in close apposition to T cells in some inflammatory processes. In this study, we analyzed whether this close physical proximity affects human mast cell degranulation and cytokine release. Thus HMC-1 human mast cells or primary bone marrow-derived human mast cells were cocultured with activated and with resting T cells. Mast cells cocultured with activated T cells released histamine and beta-hexosaminidase and produced tumor necrosis factor alpha (TNF-alpha), an effect that peaked at 20 h. Kinetics of histamine release paralleled the formation of heterotypic aggregates. Separation of the two cell populations with a porous membrane prevented mediator release and TNF-alpha production. Addition of the PI3-kinase inhibitor, wortmannin, inhibited the heterotypic adhesion-associated degranulation but not TNF-alpha production. These data thus indicate a novel pathway through which human mast cells are activated to both release granule-associated mediators and to produce cytokines in association with heterotypic adhesion to activated human T cells.
 ...
PMID:Activated T lymphocytes induce degranulation and cytokine production by human mast cells following cell-to-cell contact. 950 May 21

The aim of our study was to evaluate the sensitivity of skin mast cells from urticaria pigmentosa (UP) patients to substance P (SP), tumor necrosis factor alpha (TNF-alpha) and anti-IgE, and to compare the sensitivity of these cells with that of skin mast cells from healthy human donors. Mast cells for in vitro functional studies were obtained using an enzymatic dispersion technique from skin biopsies (from 11 patients with UP and 11 healthy donors), and the reactivity of these cells was estimated on the basis of histamine release. Our observations indicated that UP skin mast cells and healthy skin mast cells had similar sensitivities to challenge with TNF-alpha at a concentration 10(-7) M (16.4% vs 15.2%) and with anti-IgE at a dilution 1:100 (41.0% vs 37.0%). However, UP mast cells showed considerably higher sensitivity to challenge with SP at a concentration 10(-4) M than healthy skin mast cells (20.0% vs 6.8%), and the difference was statistically significant (P < 0.001). UP skin mast cells also demonstrated significantly higher spontaneous histamine release than healthy skin mast cells (32.1% vs 12.4%, P < 0.001). Our findings indicating UP skin mast cell sensitivity to SP might suggest that mechanisms involving neurogenic inflammation could contribute to the course of this disease.
 ...
PMID:In vitro reactivity of mast cells in urticaria pigmentosa skin. 952 96

Toxins A and B from Clostridium difficile are the main cause of antibiotic-associated diarrhea and pseudomembranous colitis. They cause fluid accumulation, necrosis, and a strong inflammatory response when inoculated in intestinal loops. Since mast cells are a rich source of inflammatory mediators, abundant in the gut, and known to be involved in C. difficile-induced enteritis, we studied the in vitro effect of toxin A on isolated mast cells. Normal rats sensitized by infection with Nippostrongilus brasiliensis were used to isolate peritoneal mast cells (PMC). PMC from naive rats were stimulated with calcium ionophore A23187 as a model of antigen-independent activation, and PMC from sensitized rats were stimulated with N. brasiliensis antigens to study immunoglobulin E-dependent mast cell activation. After 4 h, toxin A did not induce release of nitric oxide or histamine in naive PMC. However, 10 ng of toxin per ml caused a significant release of tumor necrosis factor alpha (TNF-alpha). In contrast, 1 microg of toxin per ml inhibited antigen or A23187-induced histamine release by PMC. Toxin A at 1 microg/ml for 4 h caused disruption of actin which aggregated in the cytoplasm and around the nucleus. After 24 h, chromatin condensation, cytoplasmic blebbing, and apoptotic-like vesicles were observed; DNA fragmentation was documented also. These results suggest that mast cells may participate in the initial inflammatory response to C. difficile infection by releasing TNF-alpha upon interaction with toxin A. However, longer exposure to toxin A affects the release of inflammatory mediators, perhaps because of the alteration of the cytoskeleton and induction of apoptosis. The impaired functions and survival of mast cells by C. difficile toxin A could hamper the capacity of these cells to counteract the infection, thus prolonging the pathogenic effects of C. difficile toxins.
 ...
PMID:Effects of toxin A from Clostridium difficile on mast cell activation and survival. 959 44

Endometrial matrix metalloproteinases (MMPs), which increase dramatically at menstruation, are purported to cause the focal tissue breakdown at menstruation, but how their expression or activation is locally regulated is unknown. Mast cell activation occurs within perimenstrual endometrium, and we postulated that mast cell products would regulate endometrial MMPs. We have examined the interaction between human mast cells and endometrial stromal cells with regard to MMP production and activation. The human mast cell line (HMC-1) in coculture with stromal cells stimulated stromal cell proMMP-1 and proMMP-3, and to a lesser extent proMMP-2 production, with increasing stimulation as mast cell number increased. Mast cell-conditioned medium also increased both protein and mRNA for stromal proMMP-1 and proMMP-3, this being abrogated by preadsorption of mast cell-conditioned medium with antisera to interleukin-1 and tumor necrosis factor alpha. Mast cell-conditioned medium added to stromal cell culture medium in vitro along with added heparin (which stabilizes tryptase activity) resulted in the appearance of molecular weight forms indicative of active MMP-3 and MMP-1. Thus activated mast cells within the endometrium prior to menstruation have the potential to stimulate MMP production by endometrial stromal cells and to initiate precursor activation, and are likely to account for the local nature of endometrial MMP action resulting in foci of tissue breakdown at menstruation.
 ...
PMID:Mast cell regulation of human endometrial matrix metalloproteinases: A mechanism underlying menstruation. 971 71

We examined the mechanisms of quinolone phototoxicity in vivo and in vitro. Simultaneous p.o. administration of a quinolone and ultraviolet-A (UVA) irradiation for 4 h induced auricular skin inflammation in BALB/c mice, including edema and neutrophil infiltration in the dermis. Antioxidants inhibited the inflammation in the early stage and cyclooxygenase inhibitors did in both the early and later stages, whereas 5-lipoxygenase inhibitors or histamine antagonists had no effect. The phototoxic inflammation was also induced in mast cell-deficient WBB6F1-W/Wv mice. Corresponding to the in vivo results, incubation with a quinolone under UVA irradiation stimulated BALB/c 3T3 mouse fibroblast cells to release prostaglandin E2 (PGE2) and 6-keto-PGF1alpha, but not leukotriene B4. In contrast, UVA-pre-irradiated quinolones did not affect PG release from fibroblasts. The PGE2 release was inhibited by cyclooxygenase inhibitors, antioxidants, protein kinase C (PKC) inhibitors and a tyrosine kinase (TK) inhibitor, but not by antibodies against tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1). These results lead to a hypothesis that reactive oxygen species generated from quinolones under UVA irradiation trigger PG release from dermal fibroblasts via PKC and TK activation, resulting in skin inflammation and that 5-lipoxygenase products, histamine, TNF alpha or IL-1 is ruled out from the mechanism.
 ...
PMID:Mechanisms of quinolone phototoxicity. 1002 81

The Lyme disease spirochete, Borrelia burgdorferi, is introduced into human hosts via tick bites. Among the cell types present in the skin which may initially contact spirochetes are mast cells. Since spirochetes are known to activate a variety of cell types in vitro, we tested whether B. burgdorferi spirochetes could activate mast cells. We report here that freshly isolated rat peritoneal mast cells or mouse MC/9 mast cells cultured in vitro with live or freeze-thawed B. burgdorferi spirochetes undergo low but detectable degranulation, as measured by [5-3H] hydroxytryptamine release, and they synthesize and secrete the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). In contrast to findings in previous studies, where B. burgdorferi-associated activity was shown to be dependent upon protein lipidation, mast cell TNF-alpha release was not induced by either lipidated or unlipidated recombinant OspA. This activity was additionally shown to be protease sensitive and surface expressed. Finally, comparisons of TNF-alpha-inducing activity in known low-, intermediate-, and high-passage B. burgdorferi B31 isolates demonstrated passage-dependent loss of activity, indicating that the activity is probably plasmid encoded. These findings document the presence in low-passage B. burgdorferi spirochetes of a novel lipidation-independent activity capable of inducing cytokine release from host cells.
 ...
PMID:Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. 1002 50


<< Previous 1 2 3 4 5 6 Next >>