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)

IP-10 is a member of the chemokine family of cytokines and is induced in a variety of cells in response to interferon gamma and lipopolysaccharide. The self-aggregation common to many chemokines, including IP-10, has hindered the identification of a specific IP-10 receptor. Using an IP-10 alkaline phosphatase fusion protein that fortuitously blocks this self-aggregation, we have identified an IP-10 binding site on a variety of cells including endothelial, epithelial, and hematopoietic cells. This binding site has a Kd of 25 nM, is inhibited by recombinant murine or human IP-10, and is dependent on the presence of cell surface heparan sulfate proteoglycans (HSPG). This conclusion is based on the findings that IP-10 binding to cells is: (a) inhibited by heparin and heparan sulfate; (b) sensitive to a 1 M NaCl wash; (c) eliminated by treatment with heparinase and trypsin; and (d) absent on mutant CHO cells that do not express cell surface HSPG. Platelet factor 4 (PF4), but not IL-8, monocyte chemoattractant protein-1, RANTES, monocyte inflammatory protein (MIP)-1 alpha, or MIP-1 beta, can compete effectively with IP-10 for binding to the cell surface. Furthermore, IP-10 shares with PF4 the ability to inhibit endothelial cell proliferation (IC50 = 150 nM). These studies demonstrate specificity in the interaction of chemokines and HSPG, and they define IP-10 and PF4 as a distinct subset of chemokines sharing an HSPG-binding site and angiostatic properties.
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PMID:The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. 779 Aug 18

The chemokines are a family of immune mediators involved in a wide range of inflammatory processes, most importantly as chemoattractants of monocytes, neutrophils, lymphocytes, and fibroblasts to sites of inflammation. Nuclear magnetic resonance and x-ray crystallographic studies have shown that IL-8 and macrophage-inflammatory protein-1 beta (MIP-1 beta) form noncovalent dimers and that platelet factor-4 (PF-4) forms noncovalent dimers and tetramers, leading to the assumption that, as a family, the chemokines would form multimeric structures. In this study, we analyze the association states of the chemokines IL-8, monocyte chemoattractant protein-1 (MCP-1), and I-309, by using a combination of size exclusion HPLC, sedimentation equilibrium ultracentrifugation, and chemical cross-linking. We find that the association states of MCP-1 and IL-8 are characterized by an equilibrium between monomers and dimers: although dimers predominate at concentrations above 100 microM, these chemokines are almost exclusively monomeric at the nanomolar concentrations at which they display maximal chemotactic activity. I-309, by contrast, remains a monomer at all concentrations tested. I-309 contains two additional cysteine residues (C26 and C68) that are not found in any other members of the chemokine family. We used cyanogen bromide and trypsin digestion strategies to demonstrate that these two residues are linked in a unique intramolecular disulfide bond. Furthermore, by using site-directed mutagenesis, we show that the integrity of this bond is crucial for protein secretion.
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PMID:The chemokines IL-8, monocyte chemoattractant protein-1, and I-309 are monomers at physiologically relevant concentrations. 807 76

HIV-1 actively replicates in dendritic cell (DC)-T cell cocultures, but it has been difficult to demonstrate substantial infection of purified mature DCs. We now find that HIV-1 begins reverse transcription much more efficiently in DCs than T cells, even though T cells have higher levels of CD4 and gp120 binding. DCs isolated from skin or from blood precursors behave similarly. Several M-tropic strains and the T-tropic strain IIIB enter DCs efficiently, as assessed by the progressive formation of the early products of reverse transcription after a 90-min virus pulse at 37 degrees C. However, few late gag-containing sequences are detected, so that active viral replication does not occur. The formation of these early transcripts seems to follow entry of HIV-1, rather than binding of virions that contain viral DNA. Early transcripts are scarce if DCs are exposed to virus on ice for 4 h, or for 90 min at 37 degrees C, conditions which allow virus binding. Also the early transcripts once formed are insensitive to trypsin. The entry of a M-tropic isolates is blocked by the chemokine RANTES, and the entry of IIIB by SDF-1. RANTES interacts with CCR5 and SDF-1 with CXCR4 receptors. Entry of M-tropic but not T-tropic virus is ablated in DCs from individuals who lack a functional CCR5 receptor. DCs express more CCR5 and CXCR4 mRNA than T cells. Therefore, while HIV-1 does not replicate efficiently in mature DCs, viral entry can be active and can be blocked by chemokines that act on known receptors for M- and T-tropic virus.
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PMID:Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. 897

The protease-activated receptor-2 (PAR-2) is a seven transmembrane domain receptor related to the thrombin receptor, which is activated in vitro by cleavage by trypsin. Affinity-purified rabbit IgG raised against a peptide corresponding to the trypsin cleavage site of PAR-2 was used for an immunohistochemical study of skin. The expression of PAR-2 in epidermis was striking, with keratinocytes showing abundant intercellular and cytoplasmic staining. Basal cells showed the strongest staining intensity and the stratum corneum was negative. Staining with control IgG used at the same concentration was consistently negative. The functional expression of PAR-2 by the simian virus transformed human skin keratinocyte cell line SVK14 was demonstrated by Northern blot analysis, flow cytometric analysis and the measurement of intracellular calcium. Treatment of SVK14 with trypsin or a receptor agonist peptide (SLIGKV-NH2) caused a dose-dependent increase in the secretion of the chemokine interleukin-8 (IL-8) in vitro. The effect of the peptide was specific, since control acetylated peptide was without activity. We conclude that PAR-2 is highly expressed by epidermal keratinocytes and receptor activation in vitro leads to increased IL-8 secretion by keratinocytes. These data raise the possibility that PAR-2 may play a role in epidermal homeostasis and inflammatory conditions.
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PMID:Immunolocalization of protease-activated receptor-2 in skin: receptor activation stimulates interleukin-8 secretion by keratinocytes in vitro. 976 17

Mast cells (MCs) arise in situ from circulating stem cell factor (SCF)-dependent committed progenitors (PrMCs) and accumulate at sites of allergic mucosal inflammation. We hypothesized that human (h)PrMCs and their mature counterparts might share overlapping patterns of chemokine and cytokine receptor utilization with eosinophils, basophils, and T helper type 2 (Th2) lymphocytes for their homing and allergy-associated hyperplasia. We have characterized committed hPrMCs and fully mature hMCs derived in vitro from cord blood for their functional responses to chemokine and cytokine agonists germane to allergic inflammation and for their maturation-related expression of the corresponding receptors. After 4 wk of culture in the presence of recombinant stem cell factor (SCF), interleukin (IL)-6, and IL-10, the cells were characterized as hPrMCs based upon their uniform surface expression of c-kit and CD13, low-level expression of FcinRIalpha, absence of CD14 and CD16 expression, and immunoreactivity for MC chymase in >80%, and about half were immunoreactive for tryptase and metachromatic with toluidine blue. By week 9, the cells had matured into hMCs, identified by higher levels of c-kit, continued expression of CD13 and low-level FcinRIalpha, uniform toluidine blue metachromasia, and uniform immunoreactivity for both tryptase and chymase. The 4-wk-old hPrMCs expressed four chemokine receptors (CXCR2, CCR3, CXCR4, and CCR5). Each receptor mediated transient rapid calcium fluxes in response to its respective ligand. Both recombinant human eotaxin and stromal cell-derived factor 1alpha elicited chemotaxis of hPrMCs. Only CCR3 was retained on the mature 9-wk-old hMCs from among these chemokine receptors, and hMCs responded to eotaxin with a sustained calcium flux but without chemotaxis. The Th2 cytokines IL-3, IL-5, IL-6, IL-9, and granulocyte/macrophage colony-stimulating factor each augmented the SCF-dependent proliferation of hPrMCs and hMCs. In contrast, the prototypical Th1 cytokine, interferon gamma, suppressed SCF-driven proliferation of both hPrMCs and hMCs. Thus, throughout their development in vitro, hMCs obey SCF-dependent, cytokine-driven mitogenic responses that reflect a Th2-type polarization characteristic of allergy and asthma. Furthermore, committed hPrMCs have a unique profile of chemokine receptor expression from among reported hematopoietic cells, including CCR3, which is shared with the other cells central to allergic inflammation (eosinophils, basophils, and Th2 lymphocytes).
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PMID:T helper cell type 2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro. 1043 89

Infection with human immunodeficiency virus type-1 (HIV-1) requires the presence of a CD4 molecule and chemokine receptors such as CXCR4 or CCR5 on the surface of target cells. However, it is still not clear how the virus enters the cells. Although CD4 was initially identified as the primary receptor for HIV-1, the expression of CD4 or one of the chemokine receptors alone is not sufficient to render susceptibility to infection with the virus. To ascertain whether or not adsorption of the virus needs charge-to-charge interaction between viral envelope and host cell membrane protein(s) and if binding alone promotes penetration of the virus into the cells, we have developed a chemically induced infection system targeting a CD4-negative and CXCR4-positive HeLa cell clone (N7 HeLa) which is usually not susceptible to infection with the LAI strain of HIV-1. Use of a poly-L-lysine (PLL)-coated culture plate to enhance the attachment of the virus to the cells made N7 HeLa cells infectable with HIV-1 at very low efficiency. PLL alone cannot fully substitute for the function of the CD4 molecule. However, trypsin-treated viruses, which have largely lost infectivity to CD4-positive MT-4 cells that are highly susceptible to HIV-1 infection, enhanced infectivity against N7 HeLa cells when the PLL-coated plate was used. These results provide evidence that infection with HIV-1 requires both high binding affinity between viruses and cells, and then needs a modification of the viral envelope such as cleavage of gp120/160 to enhance the infection, probably resulting in exposure of the hydrophobic fusion domain of gp41. HIV-1 infection of N7 HeLa cells was also enhanced by treatment with low pH, 12-O-tetradecanoylphorbol-13-acetate (TPA) and some factor(s) from the MT-4 cell culture supernatant. Not only tight viral adsorption with cleavage of the viral envelope but also some activated status of the cells may be required for sufficient HIV-1 infection in this artificial condition.
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PMID:Chemically induced infection of CD4-negative HeLa cells with HIV-1. 1065 75

In the cholecystokinin (CCK) hyperstimulation model of acute pancreatitis, two early intracellular events, activation of trypsinogen and activation of nuclear factor-kappaB (NF-kappaB), are thought to be important in the development of the disease. In this study, the relationship between these two events was investigated. NF-kappaB activity was monitored by using a DNA binding assay and mob-1 chemokine gene expression. Intracellular trypsin activity was measured by using a fluorogenic substrate. Protease inhibitors including FUT-175, Pefabloc, and E-64d prevented CCK stimulation of intracellular trypsinogen and NF-kappaB activation. Likewise, the NF-kappaB inhibitors pyrrolidine dithiocarbamate and N-acetyl-L-cysteine inhibited CCK stimulation of NF-kappaB and intracellular trypsinogen activation. These results suggested a possible codependency of these two events. However, CCK stimulated NF-kappaB activation in Chinese hamster ovary-CCK(A) cells, which do not express trypsinogen, indicating that trypsin is not necessary for CCK activation of NF-kappaB. Furthermore, adenovirus-mediated expression in acinar cells of active p65 subunits to stimulate NF-kappaB, or of inhibitory kappaB-alpha molecules to inhibit NF-kappaB, did not affect either basal or CCK-mediated trypsinogen activation. Thus trypsinogen and NF-kappaB activation are independent events stimulated by CCK.
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PMID:CCK independently activates intracellular trypsinogen and NF-kappaB in rat pancreatic acinar cells. 1117 65

Allergic rhinitis is an inflammatory disorder of the nasal mucosa typified by the symptoms of nasal itch, sneeze, anterior nasal secretions, and nasal blockage. These symptoms arise from the interaction between mediators and neural, vascular, and glandular structures within the nose. Nasal itch, sneezes, and rhinorrhoea are predominantly neural in origin, while nasal obstruction is predominantly vascular. Nasal biopsy studies show accumulation of eosinophils within the lamina propria and epithelium and an increase in tissue and cell surface basophils in both seasonal and perennial allergic rhinitis. These cells are in an activated state. Within the epithelium, increased numbers of mast cells, T cells and Langerhans' cells, which induce T-cell activation, are found. The accumulation of these cells can be linked to chemokine and cytokine generation by the epithelial cells themselves. Thus, the tissue cell recruitment is orchestrated by activated mast cells, T cells, and epithelial cells, with the recruited tissue eosinophils also contributing to their persistence at this site through autocrine mechanisms. Mast cells generate an array of mediators including histamine, tryptase, leukotrienes, and prostaglandins. Histamine is also generated by basophils. Eosinophils and basophils contribute to the leukotriene synthesis within the tissue. Histamine nasal insufflation induces nasal itch, sneeze, and rhinorrhoea as well as nasal blockage, thereby reproducing all the symptoms of allergic rhinitis. These effects are primarily mediated by H1-receptors, and H1-receptor antagonists are a prominent treatment. Antagonism of histamine at these receptors reduces symptoms by about 40-50%, with the greatest effect on the neurally mediated responses. Thus, histamine is a major mediator of allergic rhinitis, but not the sole contributor. Nasal insufflation with leukotrienes, prostaglandins, or kinins is associated with the development of nasal blockage. These mediators act primarily on the nasal vasculature and, in this respect, leukotrienes are potent mediators. Leukotrienes also induce plasma protein exudation, which contributes to the anterior nasal secretions. Studies with combination products have suggested that modifying the effects of both leukotrienes and histamine has complementary effects in relieving nasal symptoms, indicating that both these mediators are relevant to disease expression.
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PMID:Allergic rhinitis: not purely a histamine-related disease. 1129 80

Desloratadine is a new, selective, H(1)-receptor antagonist that also has anti-inflammatory activity. In vitro studies have shown that desloratadine inhibits the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, PGD(2), leukotriene C(4), tryptase, histamine, and the TNF-alpha-induced chemokine RANTES. Desloratadine also inhibits the induction of cell adhesion molecules, plateletactivating factor-induced eosinophil chemotaxis, TNF-alpha-induced eosinophil adhesion, and spontaneous and phorbol myristate acetate-induced superoxide generation in vitro. In animals desloratadine had no effect on the central nervous, cardiovascular, renal, or gastrointestinal systems. Desloratadine is rapidly absorbed, has dose-proportional pharmacokinetics, and has a half-life of 27 hours. The absorption of desloratadine is not affected by food, and the metabolism and elimination are not significantly affected by the subject's age, race, or sex. There are no clinically relevant interactions between desloratadine and erythromycin, ketoconazole, or grapefruit juice. Desloratadine is not a significant substrate of the P-glycoprotein transport system. Once daily administration of desloratadine rapidly reduces the nasal and nonnasal symptoms of seasonal allergic rhinitis, including congestion. In patients with seasonal allergic rhinitis and concomitant asthma, desloratadine treatment was also associated with significant reductions in total asthma symptom score and use of inhaled beta(2)-agonists. Use of desloratadine in patients with chronic idiopathic urticaria was associated with significant reductions in pruritus, number of hives, size of the largest hive, and interference with sleep and daily activities. Clinical experience in over 2300 patients has shown that the adverse event profile of desloratadine is similar to that of placebo; desloratadine has no clinically relevant effects on electrocardiographic parameters, does not impair wakefulness or psychomotor performance, and does not exacerbate the psychomotor impairment associated with alcohol use.
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PMID:Desloratadine: A new, nonsedating, oral antihistamine. 1129 78

Mast cells have been reported to release not only chemical mediators, but also cytokines upon Fc epsilon receptor I(Fc epsilon RI) cross-linking. Recently, we have established a culture system to derive chymase-rich human mast cells from mononuclear cells in peripheral blood. However, the functional properties of these mast cells have remained unrevealed. In this study, we examined the functions of peripheral blood-derived human cultured mast cells (pHCMCs). pHCMCs expressed functional Fc epsilon RI, and most of them contained tryptase. These pHCMCs sensitized with immunoglobulin E (IgE) and interleukin 4 (IL-4) were activated through cross-linking of Fc epsilon RI. The time-dependent mRNA expression profiles of Fc epsilon RI subunits, cytokines and chemokines in the sensitized pHCMCs upon Fc epsilon RI engagement were examined by reverse transcriptase polymerase chain reaction (RT-PCR). mRNA for most of cytokines and chemokines, which were observed in allergic inflammation, was detected in activated pHCMCs. In addition, gene expression for monocyte chemoattractant protein 3 (MCP-3) in human mast cells, and liver and activation-regulated chemokine (LARC), thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in mast cells was revealed for the first time in our study. Fc epsilon RI-mediated cytokine and chemokine production at protein level was evaluated using enzyme-linked immunosorbent assay (ELISA). These data suggest that pHCMCs, which are capable of producing a variety of cytokines and chemokines, can be a useful candidate for investigating roles of mast cells as a conductor for allergic inflammation.
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PMID:Gene expression profiles for Fc epsilon RI, cytokines and chemokines upon Fc epsilon RI activation in human cultured mast cells derived from peripheral blood. 1179 24


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