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

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant mouse mast cell protease 6 (mMCP-6) was generated to study the role of this tryptase in inflammatory reactions. Seven to forty-eight hours after the i.p. injection of recombinant mMCP-6 into BALB/c, mast cell-deficient WCB6F1-Sl/Sl(d), C5-deficient, or mMCP-5-null mice, the number of neutrophils in the peritoneal cavity of each animal increased significantly by >50-fold. The failure of the closely related recombinant tryptase mMCP-7 to induce a comparable peritonitis indicates that the substrate specificities of the two tryptases are very different. Unlike most forms of acute inflammation, the mMCP-6-mediated peritonitis was relatively long lasting and neutrophil specific. Mouse MCP-6 did not induce neutrophil chemotaxis directly in an in vitro assay, but did promote chemotaxis of the leukocyte in the presence of endothelial cells. Mouse MCP-6 did not induce cultured human endothelial cells to express TNF-alpha, RANTES, IL-1alpha, or IL-6. However, the tryptase induced endothelial cells to express large amounts of IL-8 continually over a 40-h period. Neither enzymatically active mMCP-7 nor enzymatically inactive pro-mMCP-6 was able to induce endothelial cells to increase their expression of IL-8. Although the mechanism by which mMCP-6 induces neutrophil accumulation in tissues remains to be determined, the finding that mMCP-6 induces cultured human endothelial cells to selectively release large amounts of IL-8 raises the possibility that this tryptase regulates the steady state levels of neutrophil-specific chemokines in vivo during mast cell-mediated inflammatory events.
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PMID:Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6. 946 53

CD43 has been shown to be involved in the regulation of cellular adhesion and activation of leukocytes, but its functional significance for mast cell biology has been poorly defined. We demonstrate here that mAb engagement of surface CD43 on human leukemic (HMC-1) mast cells initiates a signaling cascade which involves protein kinase C, while tyrosine kinases appear to play a minor role, as evidenced by effects of different kinase inhibitors on homotypic aggregation induced via CD43. Furthermore, administration of an activating anti-CD43 mAb is shown to induce and promote TNF-alpha- and to enhance IL-8-secretion from HMC-1 cells, but it does not initiate histamine, tryptase, or LTC4 release, suggesting that the intracellular pathways leading to aggregation and release of certain mast cell mediators are differentially regulated. Additionally, engagement of CD43 on HMC-1 cells leads to down-regulation of CD43 surface expression, implying that CD43 may be potentially involved in its own regulation.
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PMID:Signal transduction via CD43 (leukosialin, sialophorin) and associated biological effects in human mast cell line (HMC-1). 947 99

In order to explore the potential existence of human mast cell growth factors other than stem cell factor (SCF), we have compared SCF to L-cell fibroblast supernatants (LCS) during in vitro mast cell differentiation, using human leukaemic mast cells (HMC-1 cells) which contain a gain-of-function mutated SCF receptor (c-Kit) as model. At baseline, cells exhibited an immature phenotype, with <25% being metachromatic or chloroacetate esterase, tryptase and FcepsilonRIalpha positive. Intracellular levels of histamine, tryptase, TNF-alpha and chymase were low, whereas 83% of cells were c-Kit positive. During a 10 day culture with 30% LCS, a significant, time-dependent increase of all mast cell markers, except for chymase and c-Kit, was observed at the protein and for tryptase and FcepsilonRIalpha also at the mRNA level. Cytoplasmatic granulation and stimulated histamine and leukotriene C4 release were increased as well. In contrast to LCS, rhSCF induced none of these changes in HMC-1 cells. On Sephadex G100 fractionation of LCS, HMC-1 cells increased tryptase activity with fractions between 40 and 60, and below 10 kDa, away from the SCF peak. These data show that HMC-1 cells fail to differentiate in response to SCF and that in addition to SCF, LCS contains other human mast cell growth factors.
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PMID:Induction of human leukaemic mast cell differentiation by fibroblast supernatants, but not by stem cell factor. 960 Mar 13

Mast cells are found frequently in close proximity to blood vessels, and endothelial cells are likely to be exposed to high concentrations of their granule mediators. We have investigated the proinflammatory actions of the major mast cell product tryptase on HUVEC. Addition of purified tryptase was found to stimulate thymidine incorporation, but induced little alteration in cell numbers, suggesting it is not a growth factor for HUVEC. Expression of ICAM-1, VCAM-1, and E-selectin was not altered following incubation with tryptase, but the potent granulocyte chemoattractant IL-8 was released in a dose-dependent fashion in response to physiologically relevant concentrations, with maximal levels in supernatants after 24 h. The actions of tryptase on HUVEC were inhibited by heat inactivation of the enzyme, or by preincubating with the protease inhibitors leupeptin or benzamidine, suggesting a requirement for an intact catalytic site. Reverse-transcription PCR analysis indicated up-regulation of mRNA for IL-8 as well as for IL-1 beta in response to tryptase or TNF-alpha. However, tryptase was a more selective stimulus than TNF-alpha and did not induce increased expression of mRNA for granulocyte-macrophage CSF or stimulate the release of this cytokine. Leukocyte accumulation in response to tryptase may be mediated in part through the selective secretion of IL-8 from endothelial cells.
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PMID:The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells. 971 64

The microenvironment of secondary lymphoid organs consists of two major populations of cells, the lymphoid cells and a population of stromal cells that contribute to both tissue architecture and function. Interactions of both populations are essential for the development and control of humoral immune responses. In this study, stromal-cell preparations were obtained by a multistage process. This involved culturing 300-400-microm slices of human tonsil for 6-8 days at 25 degrees C, trypsin digestion of the residual explant, followed by CD45-positive-cell depletion using magnetic beads, and a final period of culture for 4 days to remove remaining nonadherent cells. Phenotyping with a panel of monoclonal antibodies revealed that the cells express HLA-DR, CD54 (ICAM-1), CD44, but no CD45 nor a range of other markers for epithelial and endothelial cells. Immunoassays of supernatants from stromal cells revealed that IL-6 was produced constitutively, and its production was increased by treatment with TNF-alpha and IFN-gamma. In contrast IL-1, IL-2, IL-4, IL-7, IL-8, IL-10, IL-12, TNF-alpha, and IFNgamma were not produced. Functional tests showed that these cells express follicular dendritic cell-like properties. Coculturing of tonsilar B cells with stromal cells resulted in enhanced proliferation and also led to increased production of immunoglobulins and IL-6, suggesting crucial signaling between these populations.
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PMID:Tonsil stromal-cell lines expressing FDC-like properties: isolation, characterization, and interaction with B lymphocytes. 981 1

This study was designed to evaluate the possible role of cytokines (IL-1 and TNF-alpha) in the pathogenesis of acute pancreatitis in the early stage of the disease and to evaluate the protective effect of the cytokine suppressive agent, FR167653, against pancreatic injuries. Acute pancreatitis was induced in rats by closed duodenal loop. However, the free passage for the gastrointestinal contents was maintained by inserting the tube into the duodenum. In this model, the survival rate was significantly decreased as compared with the control sham-operated rats at 48 h after induction of pancreatitis. Marked hyperamylasemia and a significant increase in pancreatic water and trypsin contents were observed at 24 h after induction of pancreatitis. Pancreatic subcellular redistribution of lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. However, treatment with FR167653 at a dose of 1.5 mg/kg (four times, every 6 h after induction of pancreatitis) significantly prevented all these pancreatic injuries, improving the survival rate. These results indicate that cytokines such as IL-1 and TNF-alpha may be involved in the pathogenesis of acute pancreatitis in the early stage of the disease, and that a cytokine-suppressive agent might be of therapeutic value for the treatment of acute pancreatitis.
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PMID:Cytokine suppressive agent improves survival rate in rats with acute pancreatitis of closed duodenal loop. 992 44

The direct effect of four different radiographic contrast media (RCM) on the release of C3a and C5a and the production of IL-1 alpha and TNF-alpha from vascular endothelial cells was examined in vitro. The test RCM were as follows: diatrizoate (ionic monomer), iopamidol (nonionic monomer), ioxaglate (ionic dimer), and iotrolan (nonionic dimer). These were added to serum-free medium and adjusted to a final concentration of 1% (2.8 mg Iodine/ml). Human microvascular endothelial cells were stimulated by serum-free medium containing the test RCM for eight hours. After incubation, the media were aspirated and assayed for the concentrations of C3a, C5a, IL-1 alpha and TNF-alpha. Finally, the cells were harvested by trypsin, and their viability was determined by the dye-exclusion method. Diatrizoate and iotrolan had higher C3a release than the control (p < 0.05). No increase in C5a, IL-1 alpha or TNF-alpha levels was observed with any of the tested RCM, and there was no significant difference in cell viability with any of the tested RCM. The results of this study suggest that diatrizoate and iotrolan activated the complement system through the alternative pathway by directly stimulating vascular endothelial cells. These observations suggest that a direct effect of RCM on vascular endothelium might play a role in the pathogenesis of local drug eruptions due to RCM.
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PMID:[Activation of the complement system and cytokine production by radiographic contrast media in vascular endothelial cells in vitro]. 1002 33

Patients with gliomas exhibit deficient in vitro and in vivo T cell immune activity, and human glioblastoma culture supernatants (GCS) inhibit in vitro T lymphocyte responses. Because APC are essential for initiating and regulating T cell responses, we investigated whether GCS would affect cytokines produced by monocytes and T cells from healthy donors of PBMC. Incubation of PBMC with GCS decreased production of IL-12, IFN-gamma, and TNF-alpha, and increased production of IL-6 and IL-10. The GCS-induced changes in IL-12 and IL-10 occurred in monocytes, and involved changes in IL-12 p40 and IL-10 mRNA expression. Incubation with GCS also resulted in reduced expression of MHC class II and of CD80/86 costimulatory molecules on monocytes. The immunosuppressive effects were not the result of IL-6 or TGF-beta1 that was detected in GCS. However, it was due to a factor(s) that is resistant to pH extremes, differentially susceptible to temperature, susceptible to trypsin, and has a minimum molecular mass of 40 kDa. Our findings show that glioblastoma-generated factors that are known to suppress T cell responses alter the cytokine profiles of monocytic APC that, in turn, inhibit T cell function. This model indicates that monocytes can serve as an intermediate between tumor-generated immune-suppressive factors and the T cell responses that are suppressed in gliomas.
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PMID:Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. 1020 33

Mast cells are traditionally viewed as effector cells of immediate type hypersensitivity reactions. There is, however, a growing body of evidence that the cells might play an important role in the maintenance of tissue homeostasis and repair. We here present our own data and those from the literature elucidating the possible role of mast cells during wound healing. Studies on the fate of mast cells in scars of varying ages suggest that these cells degranulate during wounding, with a marked decrease of chymase-positive cells, although the total number of cells does not decrease, based on SCF-receptor staining. Mast cells contain a plethora of preformed mediators like heparin, histamine, tryptase, chymase, VEGF and TNF-alpha which, on release during the initial stages of wound healing, affect bleeding and subsequent coagulation and acute inflammation. Various additional vasoactive and chemotactic, rapidly generated mediators (C3a, C5a, LTB4, LTC4, PAF) will contribute to these processes, whereas mast cell-derived proinflammatory and growth promoting peptide mediators (VEGF, FGF-2, PDGF, TGF-beta, NGF, IL-4, IL-8) contribute to neoangiogenesis, fibrinogenesis or re-epithelization during the repair process. The increasing number of tryptase-positive mast cells in older scars suggest that these cells continue to be exposed to specific chemotactic, growth- and differentiation-promoting factors throughout the process of tissue remodelling. All these data indicate that mast cells contribute in a major way to wound healing. their role as potential initiators of or as contributors to this process, compared to other cell types, will however have to be further elucidated.
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PMID:Mast cells and their mediators in cutaneous wound healing--active participants or innocent bystanders? 1020 16

Linear IgA bullous dermatosis (LAD) is an acquired, heterogeneous, subepidermal blistering disease characterized by linear IgA deposits at the dermoepidermal basement membrane zone (BMZ), often with circulating IgA antibodies to the BMZ. The pathogenetic mechanism, possibly related to the immunophenotype of infiltrating cells, as well as the potential role of cytokines in determining bullous lesions, have not yet been elucidated. An immunohistochemical study was performed with a large panel of monoclonal antibodies [to CD3, CD4, CD8, CD25, CD1a, CD30, CD54, CD50, endothelial leucocyte adhesion molecule-1, vascular cell adhesion molecule-1, myeloperoxidase (MPO), eosinophil cationic protein EG1 and EG2, tryptase, HLA-DR, human interleukin (IL)-3, human IL-5, human IL-8, human IL-4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte/macrophage colony-stimulating factor] using the alkaline phosphatase-antialkaline phosphatase procedure on lesional and perilesional skin of nine patients (one male, eight female; age range 8 months-80 years) with clinical, histological and immunofluorescent proven LAD. The predominant infiltrating cells, distributed mostly inside and below the bullae, were neutrophils and eosinophils which showed intense activation (MPO +, EG1 +, EG2 +). The lymphocytic infiltrate, consisting principally of CD4 +, HLA-DR + and CD30 + T cells, had a predominantly perivascular distribution. Proinflammatory cytokines, such as TNF-alpha and IFN-gamma, showed a moderate focal expression on the dermal perivascular sites; IL-8 was found to have a particularly intense staining on all the epidermal cell layers and at perivascular and vascular sites. Other cytokines, such as IL-4 and IL-5, showed a prevalent intracytoplasmic staining on some cells of the dermal infiltrate (probably mastocytes and lymphocytes), and at the dermal-epidermal separation sites there was also an intense scattered distribution of IL-5. The specific tissue lesions of LAD may be the consequence of the IgA deposits at the BMZ and also of the release of these cytokines together with tissue damage enzymes derived from neutrophils or eosinophils.
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PMID:The role of lymphocytes, granulocytes, mast cells and their related cytokines in lesional skin of linear IgA bullous dermatosis. 1035 73


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