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)

Tryptase may be a key mediator in mast cell-mediated inflammatory reactions. When mast cells are activated, they release large amounts of these tetrameric trypsin-like serine proteases. Tryptase is present in a macromolecular complex with heparin proteoglycan where the interaction with heparin is known to be essential for maintaining enzymatic activity. Recent investigations have shown that tryptase has potent proinflammatory activity, and inhibitors of tryptase have been shown to modulate allergic reactions in vivo. Many of the tryptase inhibitors investigated previously are directed against the active site. In the present study we have investigated an alternative approach for tryptase regulation. We show that the heparin antagonists Polybrene and protamine are potent inhibitors of both human lung tryptase and of recombinant mouse tryptase (mouse mast cell protease 6). Protamine inhibited tryptase in a competitive manner whereas Polybrene showed noncompetitive inhibition kinetics. Treatment of tetrameric, active tryptase with Polybrene caused dissociation into monomers, accompanied by complete loss of enzymatic activity. The present report thus suggests that heparin antagonists potentially may be used in treatment of mast cell-mediated diseases such as asthma.
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PMID:Heparin antagonists are potent inhibitors of mast cell tryptase. 1140 83

Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9-treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9-treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenate-induced excitotoxic brain lesions in mast cell-deficient P5 pups (WBB6F1/J kit(W/W-v)), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9-treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy.
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PMID:Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain. 1147 7

Mast cell tryptase is stored as an active tetramer in complex with heparin in mast cell secretory granules. Previously, we demonstrated the dependence on heparin for the activation/tetramer formation of a recombinant tryptase. Here we have investigated the structural requirements for this activation process. The ability of heparin-related saccharides to activate a recombinant murine tryptase, mouse mast cell protease-6 (mMCP-6), was strongly dependent on anionic charge density and size. The dose-response curve for heparin-induced mMCP-6 activation displayed a bell-shaped appearance, indicating that heparin acts by binding to more than one tryptase monomer simultaneously. The minimal heparin oligosaccharide required for binding to mMCP-6 was 8-10 saccharide units. Gel filtration analyses showed that such short oligosaccharides were unable to generate tryptase tetramers, but instead gave rise to active mMCP-6 monomers. The active monomers were inhibited by bovine pancreatic trypsin inhibitor, whereas the tetramers were resistant. Furthermore, monomeric (but not tetrameric) mMCP-6 degraded fibronectin. Our results suggest a model for tryptase tetramer formation that involves bridging of tryptase monomers by heparin or other highly sulfated polysaccharides of sufficient chain length. Moreover, our results raise the possibility that some of the reported activities of tryptase may be related to active tryptase monomers that may be formed according to the mechanism described here.
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PMID:Structural requirements and mechanism for heparin-induced activation of a recombinant mouse mast cell tryptase, mouse mast cell protease-6: formation of active tryptase monomers in the presence of low molecular weight heparin. 1153 57

Mast cell chymase plays important roles in inflammation and tissue remodeling. Here we show that mast cell chymase also functions as an enhancer of immunoglobulin production. In the culture of murine spleen cells stimulated with lipopolysaccharide and interleukin-4, purified rat chymase (rat mast cell protease-I; RMCP-I), at physiological concentrations, enhanced immunoglobulin E (IgE) and IgG1 syntheses but not IgG3 synthesis. The enhancement was also evident when spleen cells depleted of T cells and macrophages were employed as responding cells. Enzymatic activity of RMCP-I was required to enhance IgE and IgG1, because two inhibitors for chymotryptic enzymes, chymostatin and Y-40613, a novel chymase inhibitor, suppressed the enhanced immunoglobulin production, and phenylmethylsulphonyl fluoride, an irreversible inhibitor for serine proteases, totally abolished the enhancing effect. Furthermore, a specific inhibitor for Zn2+-dependent metalloproteases, GI 129471, could also completely inhibit the production of IgE and IgG1 that was enhanced by RMCP-I, suggesting that a metalloprotease also played an essential role in the immunoglobulin production. Our results together with others show that proteases from mast cell granules have important function not only in the efferent phase but also in the afferent phase of immune responses.
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PMID:Rat mast cell protease-I enhances immunoglobulin E production by mouse B cells stimulated with interleukin-4. 1172 48

In the Brown Norway (BN) rat, mercuric chloride (HgCl(2)) induces a T(h)2-dominated autoimmune syndrome which includes an early phase of mast cell-dependent vasculitis. We have shown in vitro that oxidative stress up-regulates IL-4 in mast cells and predisposes to degranulation. The aim of this study was to determine whether administration of antioxidants inhibits HgCl(2)-induced early vasculitis in vivo, and, if so, to examine whether modulation of the oxidative/antioxidative balance influences IgE and IL-4 expression by mast cells in situ. Groups of rats were given HgCl(2) + saline, HgCl(2) + N-acetyl-L-cysteine (NAC), saline + saline or saline + NAC respectively and blood was taken and animals killed 48 h later. NAC significantly reduced both HgCl2-induced early vasculitis and HgCl(2)-enhanced IgE expression on mast cells with a trend to a decrease in HgCl(2)-enhanced IL-4 expression in these cells. In addition, there was an increased rat mast cell protease (RMCP) II concentration in the serum after HgCl(2) injection and the elevated levels of RMCP II stimulated by HgCl(2) were totally abolished by the administration NAC in the HgCl(2) + NAC group. However, there was no significant change in serum total IgE concentrations between the HgCl(2) + saline group and the HgCl(2) + NAC group. The non-sulphydryl-containing antioxidants desferrioxamine and pyruvate demonstrated a similar effect in inhibiting HgCl(2)-induced early vasculitis. Our data show that administration of an antioxidant to BN rats reduces HgCl(2)-induced early vasculitis, suggesting that oxidative stress plays a role in the pathogenesis of HgCl(2)-induced early vasculitis. This finding may have implications for the understanding of the initiation in this experimental model of T(h)2 cell-driven autoimmunity and possibly of analogous human diseases.
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PMID:Antioxidants inhibit mercuric chloride-induced early vasculitis. 1186 63

We investigated the participation of mast cells in colitis inflammation induced by dextran sulfate sodium (DSS). The damage score and myeloperoxidase (MPO) activity were measured to confirm the occurrence of colitis. Rat mast cell protease (RMPCP) II levels in the serum were estimated as an index of mast cell degranulation. Tissue RMCP I and RMCP II levels in the rectum were also measured as markers of the numbers of connective tissue mast cells (CTMCs) and mucosal mast cells (MMCs), respectively. Administration of 4% DSS resulted in time-related increases in damage score, MPO activity and serum RMCP II levels, which were statistically significant at 7 and 11 days after treatment. Tissue RMCP I and RMCP II levels in the rectum were also increased significantly at 7 and 11 days, and 11 days, respectively after free drinking of 4% DSS. These results suggested that mast cells proliferated or the amount of protease per mast cell increased in the sites of inflammation induced by DSS, and that these mast cells may modulate the disorders observed in DSS-induced colitis.
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PMID:Participation of mast cells in colitis inflammation induced by dextran sulfate sodium. 1198 Mar 82

Mastocytosis is a common feature of helminth infection in most host species. We examined the temporal distribution and phenotype of mast cells during intestinal schistosomiasis in mice, using antibodies directed against histamine, a general mast cell marker, against mouse mast cell protease-1 (MMCP-1), a mucosal mast cell (MMC) marker, and against tryptase, a predominantly connective tissue mast cell (CTMC) marker. Ileal paraffin and/or cryosections of control, 8- and 15-week-infected mice were quantitatively analysed. In the intestinal wall of non- and unisexual infected mice, a few dispersed mast cells were detected. In infected mice, a transient increase of mast cells in the mucosa and a gradual increase in the outer muscle layer were observed. MMCP-1 expressing MMCs were predominantly present in the mucosa during the acute phase [8 weeks postinfection (p.i.)], while tryptase and histamine immunoreactivity demonstrated that two subsets of CTMCs were predominantly present in the outer muscle layer at 15 weeks p.i. (chronic phase). In conclusion, these results reveal that, in mice, both MMCs and CTMCs are involved in the inflammatory response during schistosomiasis. The recruitment of each mast cell population is time-dependent and occurs at different locations. These data suggest that mastocytosis is associated with motility-related gastrointestinal symptoms and egg excretion.
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PMID:Temporal distribution of distinct mast cell phenotypes during intestinal schistosomiasis in mice. 1206 Mar 16

Heparin-deficient mice, generated by gene targeting of N-deacetylase/N-sulfotransferase-2 (NDST-2), display severe mast cell defects, including an absence of stored mast cell proteases. However, the mechanism behind these observations is not clear. Here we show that NDST-2+/+ bone marrow-derived mast cells cultured in the presence of IL-3 synthesise, in addition to highly sulphated chondroitin sulphate (CS), small amounts of equally highly sulphated heparin-like polysaccharide. The corresponding NDST-2-/- cells produced highly sulphated CS only. Carboxypeptidase A (CPA) activity was detected in NDST+/+ cells but was almost absent in the NDST-/- cells, whereas tryptase (mouse mast cell protease 6; mMCP-6) activity and antigen was detected in both cell types. Antigen for the chymase mMCP-5 was detected in NDST-2+/+ cells but not in the heparin-deficient cells. Northern blot analysis revealed mRNA expression of CPA, mMCP-5 and mMCP-6 in both wild-type and NDST-2-/- cells. A approximately 36 kDa CPA band, corresponding to proteolytically processed active CPA, as well as a approximately 50 kDa pro-CPA band was present in NDST-2+/+ cells. The NDST-2-/- mast cells contained similar levels of pro-CPA as the wild-type mast cells, but the approximately 36 kDa band was totally absent. This indicates that the processing of pro-CPA to its active form may require the presence of heparin and provides the first insight into a mechanism by which the absence of heparin may cause disturbed secretory granule organisation in mast cells.
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PMID:Altered storage of proteases in mast cells from mice lacking heparin: a possible role for heparin in carboxypeptidase A processing. 1210 44

The immunoregulatory cytokine transforming growth factor (TGF)-beta(1) is secreted as a biologically inactive complex with latency-associated peptide, which must be modified by local factors to expose the functionally active cytokine. The epithelial integrin alpha(v)beta(6) mediates local activation of TGF-beta(1) in the lung and beta(6)(-/-) mice exhibit exaggerated pulmonary inflammation, but their response to inflammatory stimuli in the gut has not been investigated. We found that both beta(6) and TGF-beta(1) are constitutively expressed in the jejunal epithelial compartment in uninfected mice and during infection with the intestinal nematode Nippostrongylus brasiliensis. We also present data showing that beta(6)(-/-) mice are seriously compromised in their ability to mount a mucosal mast cell response after infection, and there is a significant reduction in the expression and systemic release of the granule chymase, mouse mast cell protease-1. Because in vitro expression of this chymase is regulated by TGF-beta(1), these data indicate that in the absence of alpha(v)beta(6) epithelially expressed TGF-beta(1) may not be activated, with a consequent absence of expression of mouse mast cell protease-1 and down-regulation of the mucosal mast cell response.
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PMID:Enteric expression of the integrin alpha(v)beta(6) is essential for nematode-induced mucosal mast cell hyperplasia and expression of the granule chymase, mouse mast cell protease-1. 1221 4

MITF is a basic helix-loop-helix leucine zipper-type transcription factor and is important for development of mast cells. MITF encoded by Mi(wh) allele (Mi(wh)-MITF) was mutated at a single amino acid of basic domain, and possessed a deficient but apparent DNA-binding ability. Here, we characterized the unique effects of Mi(wh)-MITF on the expression of mast cell-related genes. The expression level of mouse mast cell protease (mMCP)-4, -5, and -6 genes in Mi(wh)/Mi(wh) cultured mast cells (CMCs) was intermediate between levels of normal (+/+) CMCs and tg/tg CMCs, which did not express any MITFs. Mi(wh)-MITF appeared to show the positive transactivation effect through the remaining DNA-binding ability. On the other hand, the expression level of tryptophan hydroxylase gene was lower in Mi(wh)/Mi(wh) CMCs than in tg/tg CMCs, suggesting the inhibitory effect of Mi(wh)-MITF on the transactivation. Mi(wh)-MITF possessed dual abnormal effects on transactivation of mast cell-related genes.
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PMID:Dual abnormal effects of mutant MITF encoded by Mi(wh) allele on mouse mast cells: decreased but recognizable transactivation and inhibition of transactivation. 1222 May 16


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