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)

The role of viral respiratory infections in lactating infants and other children continues to generate controversy. The debate concerns the difference, or the apparent differences, in the natural history of wheezing. Viral infections frequently provoke wheezing episodes in non-asthmatic small children but in the majority of these the wheezing disappears without the child subsequently developing asthma. In some cases, however, the wheezing persists and in others the child has asthma. Both the role of viral infection and the mechanisms by which wheezing can be produced in a previously healthy child or exacerbated in asthmatic children are unknown. Several hypotheses have been put forward to explain the relationship between viral infections and persistent wheezing and asthma: 1. Altered immune response to various allergens, whether producing sensitization to these allergens or inhibiting tolerance response to airborne allergens. The number of such patients is increasing, among them those with bronchiolitis, asthma, positive skin tests and specific IgE antibodies. Although there is no unanimity on the matter, these patients also present elevated IL-4 levels and reduced IFN-gamma levels. 2. Induction of inflammation typical of allergic asthma. This occurs when the virus interacts with T lymphocytes; (the natural response to viral infection is Th0 and Th1 lymphocyte differentiation and release of IFN-gamma, which has antiviral properties. In children infected with respiratory syncytial virus Th2 lymphocyte differentiation is produced, which is characteristic of allergic reactions, to the detriment of Th1); epithelial cells (in these cells active viral infection activates nuclear transcription kappa-beta and nuclear IL-6 factor, producing the release of numerous pro-inflammatory cytokines and chemokines as well as expression of adhesion molecules); eosinophils (inducing variable eosinophilia which, to a certain degree, has predictive value for the persistence of wheezing) and other inflammatory cells such as neutrophils and macrophages. In the same context, during viral respiratory infection, the presence of mediators (leukotrienes, especially LTC4, histamine, prostaglandins and tryptase) are observed in respiratory secretions and a correlation between levels of specific IgE mediators can be observed. 3. Increased allergic inflammation--producing bronchial hyperreactivity, mediator release by the various inflammatory cells and neuropeptides from C-sensitive fibers, and even interfering with nitric oxide bronchodilators. In spite of all of the above, it seems that recurrent wheezing after childhood bronchiolitis is not exclusively the result of viral infection and that other factors also play a role in this disease.
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PMID:[Viral infection and asthma: immunologic mechanisms]. 1143 87

Since asthma has been recognized as a chronic inflammatory airway disease, inflammatory markers are useful tools to show the degree of allergic airway inflammation. Asthmatic airway is characterized with infiltration of activated Th2 lymphocyte, eosinophils and mast cells/basophils. Eosinophil derived proteins such as ECP, MBP and EDN are important markers indicating eosinophilic inflammation. Histamine and tryptase are the products of mast cell/basophil activation. These markers are detected in sputum, BALF, serum and urine, and increased in asthmatics. In addition to these markers, NO concentration in exhaled air, cytokines such as IL-4, IL-5, chemokines such as RANTES, eotaxin, LTE4, MMP are inflammatory markers to indicate the quality and quantity of asthmatic airway inflammation. Assessment of these markers, therefore, contributes to better control of asthmatic symptoms with appropriate therapy.
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PMID:[Airway inflammatory marker]. 1167 35

Symptoms of nasal, pharyngeal and ocular discomfort have been reported among workers in the wood surface-coating industry. Symptoms were reported more often by workers using ultraviolet radiation-curable acrylate coatings (UV coatings), which contain potential chemical sensitizers, than by those using acid-curing coatings. Furthermore, increased levels of eosinophil cationic protein (ECP) and albumin, but not tryptase, in nasal lavage from workers exposed to UV coatings have been observed. To further examine whether air contaminants present in the UV-coating industry are causing the observed increase in symptoms, the inflammatory process in the nasal mucosa of workers exposed to UV coatings was investigated. Clinical and biochemical endpoints were selected to distinguish between specific and non-specific hypersensitivity and to test the hypothesis that the symptoms were consistent with Type IV hypersensitivity. The nasal lavage and nasal biopsy were performed under local anesthetic at the workplace during working hours after a minimum of 2 h of work in both the exposed and control groups. Albumin and ECP, and the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8), were used as inflammatory markers. A multi-probe ribonuclease protection assay was used to attempt to detect cytokine variation in human nasal biopsies. The cytokine genes analyzed were TNF-alpha, GM-CSF, interferon-gamma, IL-2, IL-4 and IL-5. L32 and GAPDH were used as control genes for mRNA expression levels. Mucosal inflammation symptoms correlated with increased levels of albumin, but not with increased levels of ECP, secreted proinflammatory cytokines or cytokine gene mRNA expression. We conclude that the symptoms are non-specific and do not correlate with occupational exposure to UV coatings under the conditions of this investigation.
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PMID:Absence of proinflammatory cytokine gene expression in nasal biopsies from wood surface-coating industry workers. 1167 74

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

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18-21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.
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PMID:Tryptase inhibition blocks airway inflammation in a mouse asthma model. 1182 36

UVB irradiation can cause considerable changes in the composition of cells in the skin and in cutaneous cytokine levels. We found that a single exposure of normal human skin to UVB induced an infiltration of numerous IL-4(+) cells. This recruitment was detectable in the papillary dermis already 5 h after irradiation, reaching a peak at 24 h and declining gradually thereafter. The IL-4(+) cells appeared in the epidermis at 24 h postradiation and reached a plateau at days 2 and 3. The number of IL-4(+) cells was markedly decreased in both dermis and epidermis at day 4, and at later time points, the IL-4 expression was absent. The IL-4(+) cells did not coexpress CD3 (T cells), tryptase (mast cells), CD56 (NK cells), and CD36 (macrophages). They did coexpress CD15 and CD11b, showed a clear association with elastase, and had a multilobed nucleus, indicating that UVB-induced infiltrating IL-4(+) cells are neutrophils. Blister fluid from irradiated skin, but not from control skin, contained IL-4 protein as well as increased levels of IL-6, IL-8, and TNF-alpha. In contrast to control cultures derived from nonirradiated skin, a predominant type 2 T cell response was detected in T cells present in primary dermal cell cultures derived from UVB-exposed skin. This type 2 shift was abolished when CD15(+) cells (i.e., neutrophils) were depleted from the dermal cell suspension before culturing, suggesting that neutrophils favor type 2 T cell responses in UVB-exposed skin.
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PMID:Ultraviolet B radiation induces a transient appearance of IL-4+ neutrophils, which support the development of Th2 responses. 1193 23

Combination of stem cell factor (SCF) and interleukin-6 (IL-6) significantly promoted proliferation of human mast cells from cord blood CD34+ cells. Most of the cells, cultured in the presence of SCF and IL-6 for 10 weeks, expressed c-kit and contained a significant amount of histamine and tryptase and a low amount of chymase. Both tryptase-positive chymase-negative mast cells (MC(T)) and tryptase-positive chymase-positive mast cells (MC(TC)) were found in the same colony derived from a single cord blood CD34+ cell, suggesting that MC(T) and MC(TC) develop from common precursor cells. Single-cell culture of CD34+ cells revealed that committed mast cell progenitors are included in CD34+CD38+HLA-DR- cells. IL-4 significantly enhanced high-affinity immunoglobulin E (IgE) receptor (FcepsilonRI) alpha-chain messenger RNA expression and induced FcepsilonRI on SCF-dependent cord blood-derived human mast cells, resulting in high histamine-releasing activity upon cross-linking of FcepsilonRI. Another factor that up-regulated FcepsilonRI was IgE, and a combination of IL-4 and IgE markedly augmented FcepsilonRI expression on the mast cells. IL-4 and IgE may enhance FcepsilonRI expression by distinct mechanisms; IL-4 promotes FcepsilonRI alpha-chain gene transcription and thus increases alpha-chain protein synthesis in the cells, whereas the binding of IgE may anchor the FcepsilonRI on the cell surface, resulting in suppression of internalization of FcepsilonRI. Mast cells are progeny of hematopoietic stem cells. Recent discovery of a xenotransplantation model revealed that human hematopoietic stem cells can proliferate and differentiate into mature mast cells in the mouse skin 3 months after transplantation of human cord blood CD34+ cells, suggesting that this model may pave the way to clarification of the functions of human mast cells in vivo.
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PMID:Cytokines regulate development of human mast cells from hematopoietic progenitors. 1204 63

Ocular allergic diseases are characterized by specific activation of conjunctival mast cells with subsequent release of preformed and newly formed mediators. Mast-cell numbers on the ocular surface are increased in all forms of allergic conjunctivitis. Mast-cell activation plays a central role in the development of the ocular allergic reaction, which can be divided into an early and a late inflammatory phase. Mast-cell mediators have been measured in tears of patients suffering from various forms of allergic conjunctivitis, and in sensitized patients after specific ocular allergen challenge. Histamine and tryptase are the most studied mediators in tears of allergic patients. Several cytokines, such as IL-4 and TNF-a, are also produced and released by conjunctival mast cells, and probably play a role in the immunoregulation on the ocular surface. In vitro studies of the characteristics and biologic functions of conjunctival mast cells highlight their central role in the pathogenesis of ocular allergy, and have led to new opportunities to evaluate anti-allergic compounds. This review discusses the role of conjunctival mast cells in the development of ocular allergic diseases.
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PMID:The central role of conjunctival mast cells in the pathogenesis of ocular allergy. 1204 69

Transmembrane tryptase (TMT)/tryptase gamma is a membrane-bound serine protease stored in the secretory granules of human and mouse lung mast cells (MCs). We now show that TMT reaches the external face of the plasma membrane when MCs are induced to degranulate. Analysis of purified recombinant TMT revealed that it is a two-chain neutral protease. Thus, TMT is the only MC protease identified so far which retains its 18-residue propeptide when proteolytically activated. The genes that encode TMT and tryptase betaI reside on human chromosome 16p13.3. However, substrate specificity studies revealed that TMT and tryptase betaI are functionally distinct even though they are approximately 50% identical. Although TMT is rapidly inactivated by the human plasma serpin alpha(1)-antitrypsin in vitro, administration of recombinant TMT (but not recombinant tryptase betaI) into the trachea of mice leads to airway hyperresponsiveness (AHR) and increased expression of interleukin (IL) 13. T cells also increase their expression of IL-13 mRNA when exposed to TMT in vitro. TMT is therefore a novel exocytosed surface mediator that can stimulate those cell types that are in close proximity. TMT induces AHR in normal mice but not in transgenic mice that lack signal transducer and activator of transcription (STAT) 6 or the alpha-chain of the cytokine receptor that recognizes both IL-4 and IL-13. Based on these data, we conclude that TMT is an exocytosed MC neutral protease that induces AHR in lungs primarily by activating an IL-13/IL-4Ralpha/STAT6-dependent pathway.
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PMID:Biochemical and functional characterization of human transmembrane tryptase (TMT)/tryptase gamma. TMT is an exocytosed mast cell protease that induces airway hyperresponsiveness in vivo via an interleukin-13/interleukin-4 receptor alpha/signal transducer and activator of transcription (STAT) 6-dependent pathway. 1219 77

Fc epsilon RI cross-linkage in mast cells results in release of granule-associated mediators, such as histamine and proteases, as well as the production of numerous cytokines, including IL-6. Mast cells have been increasingly implicated in inflammatory processes where explosive degranulation is not commonly observed. Here, we show that IL-1 stimulates secretion of IL-6 without release of the granule-associated protease tryptase in normal human umbilical cord blood-derived mast cells (hCBMCs). IL-6 secretion stimulated by IL-1 in hCBMCs is potentiated by priming with IL-4 and reflects the higher levels of IL-6 secreted from human leukemic mast cell line (HMC-1). Stimulating HMC-1 cells by both IL-1 and TNF-alpha results in synergistic secretion of IL-6. IL-6 is de novo synthesized, as its secretion is blocked by inhibitors of transcription or protein synthesis. IL-1 does not increase intracellular calcium ion levels in either hCBMCs or HMC-1 cells, and IL-6 stimulation proceeds in the absence of extracellular calcium ions. Ultrastructural Immunogold localization shows that IL-6 is excluded from the secretory granules and is compartmentalized in 40- to 80-nm vesicular structures. Selective secretion of IL-6 from mast cells appears distinct from degranulation and may contribute to the development of inflammation, where the importance of IL-6 has been recognized.
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PMID:IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. 1456 62


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