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)

A number of cytokines have been reported to increase the cell motility (scatter) of cohesive cell colonies. We report here a novel scattering factor produced by human monocytes. Media from both stimulated and non-stimulated human monocytes or the monocytic cell line, U937, increased the cell motility of 2 human colon-cancer cell lines, HT115 and HT29, but not the canine epithelial cell line MDCK. Motility was assayed by cell dissociation from carrier beads and colony scattering. HT115 cells were strongly scattered by the conditioned media but not by interleukins IL-1, 2, 4, 6, 8, 10, TNF alpha, TGF beta, EGF, GM-CSF, IGF-I, PDGF, interferon-gamma. This factor is distinct from hepatocyte growth factor/scatter factor (HGF/SF), since the activity was not blocked by anti-HGF/SF antibody. The activity was reduced by treatment with acid, heat, trypsin and dithiothreitol; this, together with gel filtration, suggests that the factor is a protein (MW 40 to 60 kDa). This new factor, which is secreted from monocytes and the monocytic cell line, U937, has the ability to increase the motility of cancer cells and may be important in controlling the behaviour of tumours in vivo.
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PMID:Monocyte-conditioned media possess a novel factor which increases motility of cancer cells. 842 96

In many immunoinflammatory diseases, macrophages, by producing interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha), stimulate protease secretion in fibroblasts, thus contributing to tissue destruction. Monocyte/macrophage activation is prompted by soluble factors released by activated T cells as well as by cell-cell contact. Indeed, previous studies have shown that monocytes exposed to paraformaldehyde (PFA)-fixed, activated T cells produced high amounts of IL-1 beta. In this report, we used the T cell line HUT-78 to further characterize the T cell factor(s) responsible for monocyte activation by cell-cell contact. After subcellular fractionation, most of the activity was found in the cellular membrane fraction of PHA/PMA-stimulated HUT-78 cells, and proved to be due to glycoproteins, following trypsin digestion and tunicamycin treatment. HUT-78 cells acquired the capacity to stimulate monocytic cells after as little as 1h of stimulation. De novo protein synthesis was required for the expression of the IL-1 beta inducing factor, as shown by cycloheximide treatment. When membrane proteins of PHA/PMA-stimulated HUT-78 cells were separated on SDS-polyacrylamide gel, a peak of stimulatory activity was observed at Mr--25-35 x 10(3). By using specific cytokine inhibitors or blocking mAbs, we ascertained that cell-associated cytokines (IL-1, IL-2, IFN gamma and GM-CSF) were not involved in monocyte activation by cell contact. Anti-CD2 and -CD11a (LFA-1) mAbs partially blocked IL-1 beta production by -25% and -35%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell surface glycoproteins expressed on activated human T cells induce production of interleukin-1 beta by monocytic cells: a possible role of CD69. 849 Jan 1

Colony-stimulating factor-1 (CSF-1) is synthesized as a secreted or membrane-bound molecule. We investigated whether osteoblastic cells produce these forms of CSF-1. Glutaraldehyde-fixed cell layers supported proliferation of the macrophage cell line BAC1.2F5, suggesting the presence of membrane- or/and matrix-associated CSF-1. Furthermore, CSF-1 activity could be either extracted from the matrix or released from the cell membrane. A neutralizing antiserum against CSF-1 inhibited these activities. After labeling the cellular proteins with [35S] met/cys or [35S] SO4(2-), CSF-1 was immunoprecipitated and analyzed by SDS-PAGE. Under nonreducing conditions, bands with MW more than 200, 200, 100, and 50 kd were detected. These bands shifted to lower MW under reducing conditions. Treatment with chondroitin lyase ABC decreased the MW of the 200 kd monomer, proving the proteoglycan structure. Much smaller quantities of CSF-1 were found in the matrix extract than in the conditioned medium. Transforming growth factor beta (TGF-beta) increased both the synthesis of CSF-1 and its accumulation in the matrix. CSF-1 released with trypsin from the membrane fraction yielded on SDS-PAGE a band with MW of 60 and 30 kd under nonreducing and reducing conditions, respectively. Transcripts encoding both the secreted and the membrane-associated forms of the cytokine were detected in osteoblasts by reverse transcription polymerase chain reaction. These data indicate that osteoblastic cells produce the secreted forms, either remaining in the culture supernatant, or being associated to the matrix, and the membrane associated form of CSF-1.
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PMID:Synthesis of membrane- and matrix-bound colony-stimulating factor-1 by cultured osteoblasts. 859 91

To establish the method for generating a large number of mature human mast cells, we cultured cord blood mononuclear cells (CBMC) in several conditions in the presence of Steel factor (SF). Among several cytokines tested, IL-6 enhanced SF-dependent mast cell growth from purified CD34+ cells for more than 8 wk in culture. When CBMC were cultured instead of CD34+ cells, IL-6 enhanced the mast cell development in the presence but not in the absence of PGE2. PGE2 enhanced the SF- and IL-6-dependent development of mast cells from CBMC probably by blocking granulocyte-macrophage CSF (GM-CSF) secretion from accessory cells, because 1) PGE2, or anti-GM-CSF enhanced the mast cell development induced by SF and IL-6 from CBMC, but not from CD34+ cells; 2) GM-CSF inhibited the enhancing effect of IL-6 on the mast cell development from CD34+ cells; and 3) PGE2 inhibited GM-CSF secretion from CBMC. The mast cells cultured in the presence of SF, IL-6, and PGE2 for >10 wk were 99% pure, and seemed to be functionally mature, because 1) they contained 5.62 micrograms of histamine and 3.46 micrograms of tryptase per 10(6) cells; and 2) when sensitized with human IgE and then challenged with anti-human IgE, the cells released a variety of mediators such as histamine, and an increase in intracellular Ca2+ was found in advance of the activation of membrane movement by using a confocal laser-scanning microscope. Electron-microscopic analysis revealed that some of the cultured mast cells are morphologically mature since they filled with scroll granules and contained crystal granules.
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PMID:Selective growth of human mast cells induced by Steel factor, IL-6, and prostaglandin E2 from cord blood mononuclear cells. 868 36

The epidemiological situation of bacterial meningitis is increasing dramatically. There is no doubt that the lack of proper animal models has hampered the achievement of effective prophylactic and therapeutic means. We report the characterization of the experimental disease caused by Haemophilus influenzae type b (Hib) in mice, taking into account its importance as an etiological agent of such a type of meningitis. The high resistance of C57BL/6, CBA/ J and BALB/cJ mice to Hib infection was proven. LD50 of Hib using trypsin or iron dextran as virulence enhancement factors (VEF), both being similar and more than 1000 times lower than that without any VEF, were determined. Lesions of CNS compatible with meningitis were found in about one third of specimens. Hair bristling, conjunctivitis, diarrhea, depression and prostration were the most characteristic symptoms. The proportion of animals which die is highest on the first day, lower on the second and almost zero after 48 h of infection. Water and food intake was higher in control than in infected animals; nevertheless, there were no differences in body weight increase among the mice after 5 days post-infection. Microorganisms were isolated from CSF and blood after 6 h of infection and positive results remained according to the size of the inoculum. Despite the acuteness of the experimental disease, antibiotic treatment with internationally recommended drugs was shown to be effective. Similar results were achieved when hyperimmune serum vs. Hib was applied.
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PMID:Experimental infection by Haemophilus influenzae type b in inbred mice. 869 54

During allergic disease, leucocytes infiltrate the affected tissues and release their mediators and cytokines. In this way, the local inflammatory process is induced and maintained. Basophilic granulocytes have been demonstrated in lung and sputum of allergic asthmatics, in nasal mucosa and secretion of allergic rhinitis patients, and in skin lesions of atopic dermatitis patients. The number of basophils correlates with the severity of the disease. Analysis of mediator profiles and cellular contents of lavages of nose, skin and lung during allergic late-phase reactions (LPR) have demonstrated histamine, but not tryptase or prostaglandin D2. The histamine-containing cells have been characterized as basophilic granulocytes. This indicates that infiltrating basophils but not mast cells are activated and release their inflammatory contents in the LPR. We are interested in the cellular mechanisms that determine the degranulation of basophils during LPR. Basophil activators, such as allergens and activated complement, are not present at these sites. However, cytokines that prime basophils but do not induce degranulation, such as interleukin-5 (IL-5) and granulocyte/macrophage colony-stimulating factor (GM-CSF), have been detected at sites of LPR. We have now observed that after emptying intracellular Ca2+ stores by means of the Ca2+ adenosine triphosphatase (ATPase) inhibitor, thapsigargin, basophils become extremely sensitive to stimuli that do not affect the Ca2+ stores themselves but that induce degranulation, such as the phorbolester, phorbol myristate acetate (PMA). The most interesting finding was that although both thapsigargin and IL-3, IL-5 or GM-CSF do not induce basophil degranulation by themselves, a 2 min preincubation of basophils with thapsigargin followed by addition of one of these cytokines resulted in extensive histamine release: IL-3 induced 71 +/- 7% histamine release (conc1/2max 6 pM), IL-5 induced 43 +/- 8% histamine release (conc1/2max 41 pM) and GM-CSF induced 57 +/- 10% histamine release (conc1/2max 140 pM). Interestingly, the effect of thapsigargin could be mimicked by platelet-activating factor (PAF) (range 10(-9) to 10(-6) M), although to a lesser extent. Our results indicate that basophil degranulation in tissues during late-phase reactions might be caused by a combination of mediators or cytokines depleting Ca2+ stores, as platelet-activating factor or thapsigargin do, concurrent with activation by interleukin-3, interleukin-5 or granulocyte/macrophage colony-stimulating factor. The response of the basophils towards these cytokines might also be influenced by cell adhesion events, such as binding of basophils via integrins. This is the subject of further study.
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PMID:The role of basophils in allergic disease. 887 Oct 57

Fibroblast-derived growth factors like SCF are able to upregulate the expression of mast cell characteristics in human multilineage hematopoietic progenitor cells. Other factors, like GM-CSF, have been reported to inhibit this process, probably by the competitive recruitment of cells not belonging to the mast cell lineage. In this study, we investigated the influence of GM-CSF on immature mast cells of the HMC-1 cell line which already show low-level expression of mast cell tryptase, histamine and Fc epsilonRI alpha. Culture of HMC-1 cells with mast-cell-conditioning medium, containing fibroblast supernatants, upregulated tryptase activity, histamine contents and expression of Fc epsilonRI alpha. However, addition of GM-CSF (10 ng/ml) markedly downregulated these mast cell markers, without affecting proliferation and viability of cells. Thus, GM-CSF may provide an inhibitory signal during mast cell differentiation and probably even downregulates mast cell characteristics in more differentiated cells.
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PMID:GM-CSF downregulates expression of tryptase, Fc epsilon RI and histamine in HMC-1 mast cells. 913 May 50

The currently available respiratory topical corticosteroids are all effective at reducing the nasal symptoms of itch, sneezing, rhinorrhoea and obstruction associated with allergic rhinitis. The mechanism of action of corticosteroids is related to their anti-inflammatory activities. They have been documented to prevent fluid exudation and reduce the number of circulating inflammatory cells, including lymphocytes, mast cells, basophils, eosinophils, macrophages, and neutrophils. This occurs through multiple mechanisms, e.g. eosinophil infiltration is suppressed by preventing cytokine production, reducing local mechanisms of tissue infiltration, and decreasing eosinophil survival. Furthermore, corticosteroids also reduce preformed and newly-generated mediators (e.g. histamine, tryptase, prostanoids, leukotrienes), and inhibit production of cytokines and chemokines by inflammatory cells (e.g. IL-1 through IL-6, IL-8, RANTES, TNF-alpha, IFN-gamma and GM-CSF). The currently available corticosteroids differ pharmacologically. Fluticasone propionate appears to have the greatest affinity for the glucocorticoid receptor, and binds more quickly and dissociates more slowly from the receptor compared with other corticosteroids, suggesting a more prolonged duration of action. Its increased specificity for respiratory tissue may lead to greater potency with less potential for systemic adverse effects. Fluticasone propionate has been compared with other corticosteroids in animal models for relative topical and systemic potency, and according to these data, it has the most favourable risk-benefit ratio.
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PMID:The pharmacological basis for the treatment of perennial allergic rhinitis and non-allergic rhinitis with topical corticosteroids. 921 61

The effects of recombinant human granulocyte CSF (rhG-CSF) and recombinant human granulocyte-macrophage CSF (rhGM-CSF) on the recombinant human stem cell factor (rhSCF)-dependent development of human mast cells from fetal liver progenitors were examined. Mast cells were identified by immunohistochemical staining for tryptase and by flow cytometric analysis of surface Kit expression. Only rhGM-CSF affected mast cell development. When rhGM-CSF (1, 10, or 100 ng/ml) and rhSCF (50 ng/ml) were added to cell cultures from day 0, both the percentage and absolute numbers of mast cells were diminished after 4 wk compared with cultures exposed to rhSCF alone. Half of the maximal response was achieved at a dose of rhGM-CSF between 0.1 and 1 ng/ml. The Kit+ cells developing in the presence of rhGM-CSF and rhSCF exhibited an intensity of surface Kit expression comparable to that of cells exposed to rhSCF alone. Also, if the initial exposure to rhGM-CSF was delayed for 1 to 3 wk, attenuation of mast cell development waned. These findings are consistent with uncommitted progenitor cells being diverted to nonmast cell lineages by rhGM-CSF, while cells committed to a mast cell lineage, albeit immature, appear to be resistant to the lineage directives of rhGM-CSF. Exposure of fetal liver cells to rhGM-CSF for 1 to 3 days before addition of rhSCF further diminishes the number of mast cells that develop compared with the simultaneous addition of these growth factors on day 0. Whether administration of rhGM-CSF to humans before or together with rhSCF diminishes the mast cell hyperplasia that occurs with rhSCF alone remains to be determined.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor (CSF), but not recombinant human granulocyte CSF, down-regulates the recombinant human stem cell factor-dependent differentiation of human fetal liver-derived mast cells. 921 2

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


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