Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel growth factor for bone marrow derived murine mucosal type mast cells has been isolated from the conditioned medium of the Mlsa-reactive mouse Th cell line MLS-4.2. In proliferation assays this growth factor synergizes, like IL-4, with IL-3 on established mast cell lines and was therefore termed MEA: mast cell growth enhancing activity. MEA was characterized as a glycoprotein with a Mr range between 37,000 and 43,000. Apparent homogeneity was obtained by using a four-step purification scheme including cation exchange chromatography, Procion red affinity chromatography, IEF, and gel filtration. Inasmuch as MEA was N-terminally blocked during automated Edman-degradation, peptide fragments after digestion with trypsin were used for partial amino acid sequence determination. All evaluable MEA peptide fragments showed complete sequence homology to a recently purified and cloned novel T cell growth factor (P40/TCGF III), the mouse homologue of human IL-9.
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PMID:Purification of MEA, a mast cell growth-enhancing activity, to apparent homogeneity and its partial amino acid sequencing. 214 Mar 90

Allergic rhinitis is an increasing problem for which new and exciting therapies are being developed. These can be understood through an appreciation of the newer concepts of pathogenesis of allergic rhinitis. Allergen induces Th2 lymphocyte proliferation in persons with allergies with the release of their characteristic combination of cytokines including IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13. These substances promote IgE and mast cell production. Mucosal mast cells that produce IL-4, IL-5, IL-6, and tryptase proliferate in the allergic epithelium. Inflammatory mediators and cytokines upregulate endothelial cell adhesion markers, such as vascular cell adhesion molecule-1. Chemoattractants, including eotaxin, IL-5, and RANTES, lead to characteristic infiltration by eosinophils, basophils, Th2 lymphocytes, and mast cells in chronic allergic rhinitis. As our understanding of the basic pathophysiologic features of allergic rhinitis continues to increase, the development of new diagnostic and treatment strategies may allow more effective modulation of the immune system, the atopic disease process, and the associated morbidity.
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PMID:Pathogenesis of allergic rhinitis. 904 69

HAP2 forms a capping structure, which binds very tightly to the distal end of flagellar filaments and still allows insertion of flagellin subunits below the cap by an unknown mechanism. Terminal regions of HAP2 from Salmonella typhimurium were found to be quickly degraded by various proteases, indicating that HAP2 also possesses disordered terminal regions like other axial proteins of bacterial flagellum. Removal of these portions by trypsin results in a fragment of 40 kDa (HP40), which lacks 42 NH2-terminal and 51 COOH-terminal residues. HAP2 in solution readily associates into a decameric structure without any significant population of intermediate oligomeric forms. The HP40 fragments, however, do not form decamers, while they can assemble into pentamers, as revealed by chemical cross-linking and analytical ultracentrifugation. Decameric HAP2 also dissociates into pentamers and smaller oligomers upon a heat induced conformational transition around 36 degreesC. While the highly mobile terminal regions are immobilized in decameric HAP2 complexes, they are still largely disordered in the pentameric state. These results demonstrate that the intersubunit interactions within the pentamers are mainly through the HP40 portions, whereas the terminal regions are responsible for association of pentamers into decameric complexes. Several observations indicate that HAP2 performs its capping function as a pentamer. We suggest that binding of the pentameric HAP2 cap to the filament is mediated by the highly flexible terminal regions. Indeed, HP40 fragments are unable to cap the end of filaments, while removal of about 30 residues from both terminal regions of HAP2 results in a highly reduced capping ability. A model is presented to explain the molecular mechanism of capping, in which conformational entropy in the disordered terminal regions moderates the otherwise too tight HAP2-filament interactions to allow insertion of flagellin subunits below the cap.
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PMID:Mechanism of self-association and filament capping by flagellar HAP2. 987 59

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

It has been established that mast cells can alter their expression of granule chymases and tryptases in vivo. In vitro, a reversible cytokine regulation has so far only been demonstrated for chymases. We now show a reversible and cytokine-regulated expression of the tryptases MMCP-6 and MMCP-7 and of the chymases MMCP-1, MMCP-2 and MMCP-4 in the continuous murine mast cell line L138.8A. The L138.8A mast cells lacked expression of mRNA for mast cell-specific proteases when cultured in IL-3, and only 49% and 41% of the cells were c-kit+ and FcepsilonRI+, respectively, by flow cytometry. Kit-ligand/stem cell factor induced synthesis of the chymase MMCP-4 and the tryptases MMCP-6 and MMCP-7 and increased the fraction of c-kit+ and FcepsilonRI+ L138.8A cells to >70%. Kit-ligand-induced tryptase expression was suppressed in the presence of IL-3 or IL-9, and reversed after withdrawal of kit-ligand. IL-9 or IL-3/IL-10 promoted the formation of Alcian blue+ granules and increased the fraction of c-kit+ and FcepsilonRI+ L138.8A cells to >90%. IL-9 further induced the expression of the chymases MMCP-1, MMCP-2 and MMCP-4. Thus, the immature mast cell line L138.8A has the capacity to modulate both tryptase and chymase expression and represents the first model system to analyze the molecular regulation of tryptase expression in vitro.
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PMID:Reversible expression of tryptases in continuous L138.8A mast cells. 1106 78

We examined the effects of IL-9 on human mast cell development from CD34(+) cord blood (CB) and peripheral blood cells in serum-deprived cultures. IL-9 apparently enhanced cell production under stimulation with stem cell factor (SCF) from CD34(+) CB cells. A great majority of the cultured cells grown with SCF + IL-9 became positive for tryptase at 4 wk. In methylcellulose cultures of CD34(+) CB cells, IL-9 increased both the number and size of mast cell colonies grown with SCF. Furthermore, SCF + IL-9 caused an exclusive expansion of mast cell colony-forming cells in a 2-wk liquid culture of CD34(+) CB cells, at a level markedly greater than for SCF alone. Clonal cell cultures and RT-PCR analysis showed that the targets of SCF + IL-9 were the CD34(+)CD38(+) CB cells rather than the CD34(+)CD38(-) CB cells. IL-9 neither augmented the SCF-dependent generation of progeny nor supported the survival of 6-wk-cultured mast cells. Moreover, there was no difference in the appearance of tryptase(+) cells and histamine content in the cultured cells between SCF and SCF + IL-9. The addition of IL-9 increased numbers of mast cell colonies grown with SCF from CD34(+) peripheral blood cells in children with or without asthma. It is of interest that mast cell progenitors of asthmatic patients responded to SCF + IL-9 to a greater extent than those of normal controls. Taken together, IL-9 appears to act as a potent enhancer for the SCF-dependent growth of mast cell progenitors in humans, particularly asthmatic patients.
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PMID:IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. 1264 6

Calcium-activated potassium ion channel-3.1 (KCa3.1) plays a pivotal role in the potassium-calcium exchange involved in atopy. This study aimed to explore the impact of lentiviral-mediated shRNA silencing KCa3.1 on allergic response in a murine allergic rhinitis (AR) model. The BALB/c mice were divided into four groups: untreated AR group, negative control AR group, lentiviral KCa3.1-shRNA treated AR group and normal control group. Concentrations of ovalbumin (OVA)-specific IgE, histamine and leukotrienes C4 (LTC4) in serum, and IL-4, IL-9 and IL-17 in nasal lavage fluid (NLF) were analyzed. Goblet cells and mast cells were counted. KCa3.1 positive cells were counted after immunolabelling by immunofluorescence method. KCa3.1, Mucin 5AC (MUC5AC), and tryptase mRNA levels were determined using real-time polymerase chain reaction. Furthermore, P815 cell line was used to explore the role and mechanism of lentiviral KCa3.1-shRNA on mast cells. The results showed that LV-KCa3.1-shRNA intervention effectively attenuated allergic responses in LV-KCa3.1-shRNA treated mice. LV-KCa3.1-shRNA intervention effectively suppressed KCa3.1 levels and phosphorylation of AKT in P815 cells, leading to the downregulation of tryptase, IL-6 and IL-8 levels. LV-KCa3.1-shRNA intervention effectively attenuated the allergic responses in AR and suppressed mast cell activity by inhibiting PI3K/AKT signaling pathway.
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PMID:Lentiviral shRNA against KCa3.1 inhibits allergic response in allergic rhinitis and suppresses mast cell activity via PI3K/AKT signaling pathway. 2627 20

Determining inflammation and itch pathway activation in patients with atopic dermatitis (AD) is fraught with the inability to precisely assess the age of skin lesions, thus affecting the analysis of time-dependent mediators. To characterize inflammatory events occurring during early experimental acute AD lesions, biopsy samples were collected 6, 24, and 48 hours after epicutaneous application of Dermatophagoides farinae house dust mites to sensitized atopic dogs. The skin transcriptome was assessed using a dog-specific microarray and quantitative PCR. Acute canine AD skin lesions had a significant up-regulation of genes encoding T helper (Th) 2 (e.g., IL4, IL5, IL13, IL31, and IL33), Th9 (IL9), and Th22 (IL22) cytokines as well as Th2-promoting chemokines such as CCL5 and CCL17. Proinflammatory (e.g., IL6, LTB, and IL18) cytokines were also up-regulated. Other known pruritogenic pathways were also activated: there was significant up-regulation of genes encoding proteases cathepsin S (CTSS), mast cell chymase (CMA1), tryptase (TPS1) and mastin, neuromedin-B (NMB), nerve growth factor (NGF), and leukotriene-synthesis enzymes (ALOX5, ALOX5AP, and LTA4H). Experimental acute canine house dust mite-induced AD lesions exhibit an activation of innate and adaptive immune responses and pruritogenic pathways similar to those seen in humans with acute AD, thereby validating this model to test innovative therapeutics modalities for this disease.
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PMID:Early Activation of Th2/Th22 Inflammatory and Pruritogenic Pathways in Acute Canine Atopic Dermatitis Skin Lesions. 2734 34

This study aimed to elucidate the role of PDIA3 in visceral hypersensitivity of rats with irritable bowel syndrome (IBS). Fourty eight SD rats were randomly divided into four groups (n=12): control group, IBS-empty virus group (IBS-1), IBS-PDIA3 silence group (IBS-2), and IBS-the control group (IBS-3). Visceral hypersensitivity models were established by using acetic acid enema combined with restraint stress, and assayed by abdominal withdrawal reflexes (AWR). Mast cells (MCs) in ileocecal mucosa were counted with toluidine blue staining. Degranulation of MCs was observed under electron microscopy. Serum and mucosal levels of IL-4 and IL-9 were measured with ELISA and QT-PCR. Intestinal tryptase and PAR-2 expression was examined with ELISA and Western blot. The Results showed that PDIA3 plays an important role in the formation of visceral hypersensitivity by increasing systemic and colon mucosal expressions of IL-4 and IL-9, activating mast cells and upregulating PAR-2 expression of target organs.
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PMID:Effect of PDIA3 gene silence on colonic mast cells and visceral sensitivity of rats with irritable bowel syndrome. 3196 10

The incidence of pancreatitis (AP) is increasing and there is no specific treatment available. Intracellular digestive enzyme activation is a key event in the pathogenesis of AP downstream of cytosolic calcium overload and impaired autophagy. Siraitia grosvenorii (Swingle) was used in Traditional Chinese Medicine to reduce inflammation and facilitate bowel movement. The bioactive components of this plant show hypolipedimic, antidiabetic, antifibrotic activity and have been used against pancreatic cancer. Here, we examined whether mogroside IIE, a major bioactive component of unripe S. grosvenorii fruit, can protect against AP. We found that mogroside IIE decreased the activity of trypsin and cathepsin B induced by cerulein plus lipopolysaccharide (LPS) in the pancreatic acinar cell line AR42J and primary acinar cells in a dose- and time-dependent manner. Mogroside IIE treatment decreased the levels of serum lipase and serum amylase in mice injected with cerulein plus LPS without influencing inflammation significantly. A multi-cytokine array revealed that mogroside IIE decreased the level of interleukin 9 (IL-9) in AP mice. Exogenous IL-9 eliminated the mogroside IIE induced reduction of trypsin and cathepsin B activity and reversed the inhibition of cytosolic calcium and modulation of autophagy mediated by mogroside IIE. An IL-9 receptor antibody neutralized the effect of IL-9, restoring mogroside IIE activity. The mogroside IIE targeted IL-9 may partially arise from Th9 cells. Taken together, we provide experimental evidence that mogroside IIE ameliorates AP in cell models and mice through downregulation of the IL-9/IL-9 receptor pathway.
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PMID:Mogroside IIE Inhibits Digestive Enzymes via Suppression of Interleukin 9/Interleukin 9 Receptor Signalling in Acute Pancreatitis. 3258 18


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