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)

It is now widely accepted that asthma in its varied forms is an inflammatory disorder of the airways in which mediator release from activated mast cells and eosinophils plays a major role. T lymphocytes take a primary role in orchestrating these processes through their capacity to generate a range of cytokines of the interleukin 4 gene cluster encoded on the long arm of chromosome 5. Additional cytokines derived from mast cells and eosinophils also play a key role, especially tumour necrosis factor alpha, which is responsible for initiating the up-regulation of vascular adhesion molecules involved in the recruitment of eosinophils and other inflammatory cells from the circulation. The importance of C-X-C and C-C chemokines as local chemoattractants and activating stimuli is also recognized. In addition to releasing an array of pharmacologically active autacoids, the inflammatory response in asthma results in the generation of proteolytic activities from mast cells (tryptase, chymase), eosinophils (MMP-9) and the epithelium itself (MMP-2, MMP-9), which exert tissue-destructive and cell-signalling effects. The epithelium is also highly activated, as evidenced by the up-regulation of cytokine production, inducible enzymes and soluble mediators. Increased surface expression of the epithelial isoform of CD44 (9v) and subepithelial proliferation of myofibroblasts are indicative of a simultaneous active repair process and the laying down of new interstitial collagens. Together, inflammatory and repair processes create the complex phenotype that characterizes asthma and its progression.
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PMID:Asthma: a dynamic disease of inflammation and repair. 925 3

Glomerular epithelial cells (GEC) and mesangial cells (MC) are both involved in glomerular diseases. To elucidate potential interactions between these glomerular cell types, we examined whether products of GEC affect the proliferative activity of MC. We found that cultured rat GEC secrete soluble factors into the supernate (GEC-CM) that induce proliferation of quiescent rat MC. The mitogenic activity was trypsin sensitive and partially heat-labile. Biochemical analysis of GEC-CM by gel filtration HPLC, reverse phase HPLC, and isoelectric focusing revealed at least three mitogenic fractions as well as inhibitory activity present in GEC-CM. Competitive binding assays with 125I-labeled PDGF did not show significant amounts of PDGF in GEC-CM. The biochemical features of the GEC-derived MC growth factors are distinct from IL-6, PDGF, bFGF, and endothelin, previously described GEC-derived MC growth factors. Additionally, significant contributions of known growth factors such as IL-1, IL-2, IL-3, IL-4, IL-5, TNF alpha, TGF beta, and GM-CSF are unlikely. The results indicate that GEC produce several biochemically-distinct MC growth regulators. While these epithelial cell-derived mitogens for MC require further characterization, they may play an important role in the regulation of MC replication, such as during embryogenesis and glomerular disease.
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PMID:Glomerular epithelial cell products stimulate mesangial cell proliferation in culture. 929 Nov 94

The effect of recombinant human IL-4 (rhIL-4) on the development of recombinant human stem cell factor-dependent fetal liver-derived mast cells was examined. RhIL-4 attenuates the number of mast cells that develop, preferentially affecting the MC(T) type of mast cell. Cellular levels of tryptase and chymase mRNA normalized to that of glyceraldehyde-3-phosphate dehydrogenase were not appreciably affected. Tryptase mRNA levels peaked at least 2 wk before tryptase protein and before chymase mRNA and protein, indicating that tryptase mRNA expression is an early marker of commitment to a mast cell lineage. In contrast, alpha-tryptase and beta-tryptase mRNA levels increased and decreased in parallel. The most dramatic effect of rhIL-4 was to induce expression of functional surface Fc epsilonRI. Expression was maximal by 21 days with 20 ng/ml of rhIL-4 and reached a plateau by 2 ng/ml of rhIL-4 at 4 wk. Fc epsilonRI+ cells increased modestly when myeloma IgE was added to the developing mast cells, but increased synergistically when both myeloma IgE and rhIL-4 were present together. Delayed addition of rhIL-4 progressively diminished Fc epsilonRI expression, as did withdrawal of rhIL-4 during the first 2 wk of culture. RhIL-4 selectively increased Fc epsilonRI alpha mRNA levels at least 10-fold. Mast cells developed in the presence of rhIL-4 released tryptase when exposed to anti-Fc epsilonRI alpha. In conclusion, induction of functional Fc epislonRI on recombinant human stem cell factor-dependent human fetal liver-derived mast cells by rhIL-4 harmonizes with the well-accepted ability of this cytokine to enhance IgE production by B cells.
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PMID:Effect of recombinant human IL-4 on tryptase, chymase, and Fc epsilon receptor type I expression in recombinant human stem cell factor-dependent fetal liver-derived human mast cells. 930 Jul 15

In all mammalian species investigated so far, mast cells and basophils are the only cells that synthesize histamine and express plasma membrane receptors that bind IgE with high affinity (Fc epsilonRI). Human basophils and mast cells derive from distinct precursors that originate in the bone marrow and fetal liver and probably circulate in peripheral blood. There is extensive evidence that mast cells and basophils and their mediators are primary effectors of allergic inflammation. Immunologically activated human basophils release two cytokines: IL-4 and IL-13. Expression of several cytokines has been documented in a number of experimental models of human and rodent mast cells. However, to date few studies have analyzed the mechanisms of gene expression in human Fc epsilonRI+ cells. Some of these studies imply a role for NFAT and GATA family members in the IgE-mediated activation of cytokine gene transcription in basophils and mast cells. Studies of human basophils and mast cells isolated from different anatomic sites have established the different profiles of eicosanoids released by these cells. Recently, the characterization of arachidonic acid pools and the identification of novel enzymes involved in arachidonate remodeling and mobilization clarified in part how eicosanoid productions is regulated in mast cells and basophils. In addition to histamine, human mast cell secretory granules contain the neutral proteases tryptase, chymase and carboxypeptidase that possess several biochemical properties. In particular, tryptase may play a role as a fibrogenic factor and chymase might convert angiotensin I to angiotensin II. Mast cells are present in human heart and in human coronary arteries raising the possibility that local activation of cardiac mast cells might contribute to certain cardiovascular diseases. Recent evidence also suggests that mast cells and basophils can play a role during viral and bacterial infections. It is now evident that in man these two cells not only participate in inflammation associated with allergic disease, but also in chronic and fibrotic disorders affecting several organs and in host defense against bacterial and viral infections.
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PMID:Molecular and cellular biology of mast cells and basophils. 936

Human cultured mast cells (HCMCs) grown from cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6) expressed tryptase but no or low chymase in their cytoplasm. The addition of IL-4 to these cells strikingly increased chymase expression. Consequently, the activity of chymase was significantly higher in IL-4-treated mast cells than that in IL-4-nontreated mast cells, whereas the activity of tryptase and histamine content were comparable in both cells. Electron microscopic immunocytochemistry also showed that secretary granules containing chymase increased in IL-4-treated mast cells. Interestingly, the IL-4-induced increase of chymase expression in HCMCs was accompanied by morphological maturation of the cells. Cytoplasmic projections were few in IL-4-nontreated HCMCs, and a small number of secretary granules were observed, most of which were empty or partially filled with discrete scrolls with rough particles showing immaturity. In contrast, IL-4-treated HCMCs had extremely abundant cytoplasmic projections and had many secretary granules filled with electron-dense crystal materials. Taken together, immature HCMCs grown only with SCF and IL-6 expressed tryptase with no or a low amount of chymase, and addition of IL-4 promoted cell maturation together with the expression of both tryptase and a high amount of chymase. Our findings will raise a possibility of a linear pathway of human mast cell development from tryptase single positive mast cells into tryptase and chymase double positive mast cells as the cells mature and will suggest that this maturation process is promoted by IL-4.
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PMID:Interleukin-4 promotes the development of tryptase and chymase double-positive human mast cells accompanied by cell maturation. 941 84

It has previously been shown that cells mRNA+ for T(H2)-type cytokines (IL-4 and IL-5) infiltrate the site of allergen-induced cutaneous late-phase reactions (LPR) in atopic subjects. In this study we have used the same experimental model to identify the cell source of both IL-4 and IL-5 mRNA and protein product. Allergen-induced LPRs were provoked in the skin of atopic individuals and the sites microscopically examined at 6, 24, and 48 hours. Using single in situ hybridization and immunohistochemistry, we first showed that the numbers of IL-4 and IL-5 mRNA and protein product positive cells peaked at 24 hours. This coincided with the magnitude of the LPR. By double in situ hybridization/immunohistochemistry, we then established (in 24-hour biopsy specimens) that the percentage of CD3+ T lymphocytes, EG2+ eosinophils, and tryptase-positive mast cells that were either IL-4 or IL-5 mRNA+ was 19%, 24%, and 5% and 19%, 20%, and 5%, respectively. Conversely, the percentage of EG2+ and tryptase-positive cells that were IL-4 or IL-5 protein product positive were 62% and 53% and 72% and 29%, respectively. IL-4 and IL-5 protein did not colocalize to CD3+ cells. CD68+ macrophages were negative in both in situ hybridization and immunohistochemistry. With eosinophils we obtained direct evidence of time-dependent stimulus-induced IL-4 and IL-5 mRNA transcription by semiquantitative reverse transcription-polymerase chain reaction of cells incubated with either IgG- or sIgA-coated particles in vitro. Taken together, these experiments suggest that eosinophils, mast cells, and T cells all contribute in variable degrees to the expression of IL-4 and IL-5 in human cutaneous LPR. The failure to colocalize IL-4/IL-5 protein (as opposed to mRNA) to CD3+ cells is attributed to the inability of T lymphocytes to store and concentrate sufficient intracellular amounts of these cytokines to produce positive immunostaining.
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PMID:IL-4- and IL-5-positive T lymphocytes, eosinophils, and mast cells in allergen-induced late-phase cutaneous reactions in atopic subjects. 950 Jul 56

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

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

Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface-bound IL-15 is upregulated upon interferon-gamma stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-alpha, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.
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PMID:Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15. 1023 6

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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