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)

Haptoglobin (Hp) is an acute phase reactant produced by hepatocytes. There is evidence for an immunomodulatory potential of Hp, though there is no clear evidence yet about the mechanisms of this action. We have previously shown that Hp interacts with the beta2-integrin CD11b/CD18. In addition, other investigators reported the binding of Hp to B lymphocytes through the CD22 receptor, and to neutrophils through two different receptors. In the present study, we investigated the interaction of haptoglobin with the human mast cell line HMC-1. We report that fluorescein isothiocyanate (FITC)-labelled haptoglobin binds to this cell line and that binding is increased by calcium in a dose- and time-dependent manner. Hp binding sites on HMC-1 were upregulated upon stimulation with phorbol myristate acetate (PMA)/A23187 and after treatment with anti-CD43 and anti-CD44 monoclonal antibodies (MoAbs). HMC-1 cells do not express either CD11b/CD18 or CD22 receptors, indicating that the haptoglobin-binding receptor on this cell line is different from the known receptors. Assessment of cell function showed that Hp inhibits the spontaneous growth of HMC-1 up till 40% at higher Hp concentrations, but it did not exhibit any effect on the expression of CD54 on the release of either tryptase or IL-1ra. In conclusion, haptoglobin binds specifically to human mast cells via a receptor different from CD11b/CD18 and CD22, and may play a role in the modulation of mast cell functions. Exploration of Hp effects in mast cell-dependent diseases such as allergic rhinitis and urticaria seems warranted.
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PMID:Haptoglobin interacts with the human mast cell line HMC-1 and inhibits its spontaneous proliferation. 1196 16

Proteinase 3 (PR3), a 29-kDa serine proteinase secreted from activated neutrophils, also exists in a membrane-bound form, and is suggested to actively contribute to inflammatory processes. The present study focused on the mechanism by which PR3 activates human oral epithelial cells. PR3 activated the epithelial cells in culture to produce IL-8 and monocyte chemoattractant protein-1 and to express ICAM-1 in a dose- and time-dependent manner. Incubation of the epithelial cells for 24 h with PR3 resulted in a significant increase in the adhesion to neutrophils, which was reduced to baseline levels in the presence of anti-ICAM-1 mAb. Activation of the epithelial cells by PR3 was inhibited by serine proteinase inhibitors and serum. The epithelial cells strongly express protease-activated receptor (PAR)-1 and PAR-2 mRNA and weakly express PAR-3 mRNA. The expression of PAR-2 on the cell surface was promoted by PR3, and inhibited by cytochalasin B, but not by cycloheximide. PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca(2+) mobilization, and rendered cells refractory to subsequent stimulation with PR3 and vice versa. The production of cytokine induced by PR3 and the PAR-2 agonist peptide was completely abolished by a phospholipase C inhibitor. These findings suggest that neutrophil PR3 activates oral epithelial cells through G protein-coupled PAR-2 and actively participates in the process of inflammation such as periodontitis.
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PMID:Activation of human oral epithelial cells by neutrophil proteinase 3 through protease-activated receptor-2. 2030 33

Fexofenadine is a non-sedating selective third-generation antihistamine, which also exerts an anti-inflammatory action. The aim of this study was to evaluate the influence on the expression of inflammatory skin mediators, together with the efficacy and tolerability, of fexofenadine in chronic idiopathic urticaria (CIU). Fexofenadine 180mg was administered once daily for 4 weeks after a placebo run-in phase of 3 to 7 days. Efficacy paramaters were obtained from patients' assessment of urticaria symptoms. Non-lesional skin of patients with active CIU was studied immunohistochemically before and after treatment. The expression of the following mediators was evaluated: adhesion molecules (ICAM-1, ELAM-1, VCAM-1); mast cell proteases (chymase and tryptase) and proinflammatory cytokines (IL-1beta, IL-3, IL-6 and TNF-alpha). Of the 20 subjects enrolled, 3 dropped out of the study. Treatment proved successful in most cases (88.2%) (p <0.01) and a significant improvement of all symptoms was registered. Treatment was well-tolerated by all patients; adverse events, neither serious nor drug-related, occurred in any case. Immunochemistry revealed at the baseline a significant expression of ELAM-1, VCAM-1, tryptase, chymase, and TNF-alpha (p= 0.05) in non-lesional skin of patients compared to normal controls. After treatment with fexofenadine, there was a significant decrease in the expression of ELAM-1 (p= 0.02), VCAM-1 (p= 0.04) and tryptase (p= 0.04), whereas no relevant change was observed for the other parameters examined. This work confirms the efficacy and tolerability of fexofenadine HCl 180mg in CIU. These preliminary data show a trend towards a decrease in the expression of tryptase and some adhesion molecules after treatment, suggesting an anti-inflammatory activity of fexofenadine.
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PMID:Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation. 1257 22

Interstitial cystitis (IC) is a sterile, painful bladder disorder, often associated with inflammation. A defective urothelium and activated mast cells have been implicated in the pathophysiology of IC. Mast cells have been reported to induce the expression of intercellular adhesion molecules (ICAM) that are considered a necessary first step for the initiation of inflammation. We investigated the presence of ICAM-1 and its association with bladder mast cells in IC patients and controls in order to further understand their role in the pathophysiology of IC. Bladder tissue was fresh frozen and 7m section were cut using a cryostat. Immunocytochemical detection was carried out with monoclonal antibodies directed against anti-ICAM1 and tryptase. Twenty-one biopsies from women with IC and two from normal tissue from radical cystectomies (control) were analyzed. All IC samples were strongly positive for ICAM-1, exclusively in capillaries. Control samples were only faintly positive in fewer capillaries. Numerous mast cells were identified in the positive regions with toluidine blue or tryptase immunocytochemistry. This work may help explain why many IC patients develop sterile inflammation. It may also provide evidence further explaining the role of bladder mast cells in the pathophysiology of IC.
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PMID:Increased expression of intercellular adhesion molecule 1 in relation to mast cells in the bladder of interstitial cystitis patients. 1278 46

In approximately one-third of patients with chronic idiopathic urticaria (CIU), autoantibodies against the high-affinity IgE receptor and/ or against IgE can be detected and a wheal-and-flare response can be provoked by the intradermal injection of autologous serum (ASST). In this study we aimed to further characterize the inflammatory response observed in the subgroup of CIU patients with positive ASST and serum-evoked histamine-release in vitro from basophils in comparison with unaffected skin and healthy donors. An immunohistochemical analysis of infiltrating cells (CD4, MPO, EG1, EG2, tryptase), cytokines (IL-4, IL-5, IFN-gamma), chemokines and chemokine receptors (IL-8, CCR3, CXCR3), and adhesion molecules (ICAM-1, VCAM-1, ELAM-1) was performed on seven selected patients (four males and three females; median age: 45 years; range: 22-57) and five healthy donors. Cytokine evaluation was also performed in five psoriatic patients to obtain an additional control. In spontaneous wheals we observed an increased number of CD4+ T lymphocytes when compared with the controls, and an increased number of neutrophils and eosinophils, whereas mast cells did not show a significant variation. A significant expression for IL-4 and IL-5 could only be observed in lesional skin, while IFN-gamma showed a slight expression in the same site. Chemokine receptors CCR3 and CXCR3 did not show a defined polarized response in either lesional or unaffected skin. An increased expression of all cellular adhesion molecules (CAMs) studied was detected in spontaneous wheals. The lack of a significant difference in the expression of tryptase + mast cells, T lymphocytes, IL-8, CXCR3 and CCR3, a few CAMs between the lesional and unaffected skin of CIU patients suggests a wide immunological activation that involves not only lesional tissues, but possibly extends to the whole of the skin's immune system.
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PMID:Infiltrating cells and related cytokines in lesional skin of patients with chronic idiopathic urticaria and positive autologous serum skin test. 1470 3

Type 1, or cellular, immune response is characterized by overproduction of TNF-alpha, IFN-gamma, IL-1, IL-2 and IL-8 and is the underlying immune mechanism of psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune uveitis (EAU). Type 2 immune response is seen in antibody-mediated autoimmune diseases. Based on the pharmacokinetic effects of cetirizine and allopurinol, this paper introduces these two safe and inexpensive drugs as novel potential agents against cell-mediated autoimmune disorders. Cetirizine, supposed to inhibit DNA binding activity of NF-kappa B, inhibits the expression of adhesion molecules on immunocytes and endothelial cells and the production of IL-8 and LTB4, two potent chemoattractants, by immune cells. It induces the release of PGE2, a suppressor of antigen presentation and MHC class II expression, from monocyte/macrophages and reduces the number of tryptase positive mast cells in inflammation sites. Tryptase is a chemoattractant, generates kinins from kininogen, activates mast cells, triggers maturation of dendritic cells and stimulates the release of IL-8 from endothelial cells and the production of Th1 lymphokines by mononuclear immunocytes. Allopurinol is a free radical scavenger, suppresses the production of TNF-alpha and downregulates the expression of ICAM-1 and P2X(7) receptors on monocyte/macrophages. ICAM-1 serves as a ligand for LFA-1 (on T lymphocytes), allowing proper antigen presentation. P2X(7) receptors are thought to be involved in IL-1beta release, mitogenic stimulation of T lymphocytes and the probable cytoplasmic communication between macrophages and lymphocytes at inflammation sites. Allopurinol was markedly more effective than prednisolone in treating experimental autoimmune uveitis and in combination with cyclosporine suppressed the inflammatory reaction of this condition more effectively than either agent alone. As allopurinol is a competitive inhibitor of xanthine oxidase and decreases serum levels of uric acid, which is protective against multiple sclerosis, it should preferably be coadministered with uric acid precursors in the treatment of this condition. Cetirizine and allopurinol may prove of benefit in the treatment of various cellular autoimmune disorders.
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PMID:Cetirizine and allopurinol as novel weapons against cellular autoimmune disorders. 1503 12

Schistosoma mansoni eggs trapped in the liver of an infected host cause the major pathological manifestations of schistosomiasis. Miracidia within the deposited eggs secrete soluble egg antigens (SEA) that induce periovular granuloma formation, which may lead to severe hepatic fibrosis. Several reports have highlighted the immunomodulatory capacities of carbohydrate determinants present in the glycoproteins of SEA. These glycans contain among others the immunogenic Galbeta1-4(Fucalpha1-3)GlcNAc (LewisX) and GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAc (LDN-DF) elements. Due to cross-reactivity with schistosomal glycan antigens, keyhole limpet haemocyanin (KLH) has been used extensively for diagnostic and therapeutic studies on schistosomiasis. In the present study, a granulomatous response with numerous eosinophils towards SEA- and KLH-coated beads implanted in the liver by mesenteric injection was observed. Immunophenotyping of these experimentally induced granulomas for cellular recruitment, chemokines, adhesion and extracellular matrix proteins revealed very close resemblance with hepatic lesions evoked by native schistosome eggs, hence demonstrating the usefulness of the bead model, in general, as well as of KLH as a model antigen to study the immunopathological mechanisms of schistosome infections. While trypsin digestion of KLH did not alter its antigenic characteristics, beads coated with SEA or KLH treated with sodium periodate to destroy the immunological properties of their carbohydrate chains, yielded only a monolayer of macrophages similar to negative control beads. Up-regulation of ICAM-1, LFA-1 and fibronectin in SEA-induced granulomas and in native and trypsinised KLH-induced granulomas indicates a major role of the carbohydrate elements of SEA and KLH in the initiation and homeostasis of the inflammatory response. These data provide new insights in the complex and multifactorial carbohydrate-dependent host-parasite immunological interactions.
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PMID:Glycans of Schistosoma mansoni and keyhole limpet haemocyanin induce hepatic granulomas in vivo. 1521 34

In acute pancreatitis, ICAM-1 is upregulated in various organs and contributes to the development of organ injury. To investigate the effects of pancreatic proteases on ICAM-1 expression and their role in the early process of leukocyte migration, human umbilical vein endothelial cells (HUVECs) were incubated with serum subjected to limited trypsin digestion and Wistar rats were injected with trypsin. Significant upregulation of membrane-bound ICAM-1 was seen on HUVECs incubated with trypsinated serum. Likewise, soluble ICAM-1 increased in the supernatant of HUVECs. Changes of membrane-bound ICAM-1 and soluble ICAM-1 were maximal with high concentrations of trypsin. HUVECs incubated with TNF-alpha (positive control) showed similar changes. In the pancreas and lungs of animals infused with trypsin, ICAM-1 and leukocyte sequestration were increased compared with controls. Reflecting the relevance of protease-induced ICAM-1 expression in leukocyte migration, leukocyte-endothelium interaction, as assessed by intravital microscopy, was markedly increased by trypsin. Inhibition of ICAM-1 ameliorated these changes significantly. In conclusion, trypsinated serum induces the upregulation of both membrane-bound ICAM-1 on endothelial cells and soluble ICAM-1. These changes contribute to the early steps of leukocyte migration in acute pancreatitis. The role of soluble ICAM-1 remains to be investigated.
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PMID:Membrane-bound ICAM-1 is upregulated by trypsin and contributes to leukocyte migration in acute pancreatitis. 1530 72

The term chronic autoimmune urticaria (CAIU) is used for chronic urticaria in subjects who present a whealing response to the intradermal injection of autologous serum, suggesting the presence of pathogenic antibody activities. In this study, we examined 28 chronic urticaria subjects with positive autologous serum skin test (ASST), all of whom presented autologous serum-induced lesions at different evolutive stages. Punch biopsies were taken from lesional skin of six subjects at 10', eight subjects at 30', six subjects at 60', and four subjects each at 24 and 48 h. Immunological studies focussed on infiltrating cell immunophenotype and related cytokines, chemokines and chemokine receptors, adhesion molecules. Immunohistochemical staining was performed to measure expression of CD3, CD4, CD8, tryptase, eosinophil cationic protein, myeloperoxidase, basophil granular protein, IL-4, IL-5, IL-8, CCR3 and CXCR3, ICAM-1, VCAM and ELAM. Control staining was done on unaffected skin from the patients and normal skin from four healthy donors. The main infiltrating population was represented by neutrophils, seen focally in both unaffected skin (P = 0.001) and healthy controls (P = 0.003). IFN-gamma and IL-5 were expressed focally in autologous wheals. Significant staining for IL-4 was seen at 30'. CCR3 and CXCR3 were expressed less in autologous wheals than in uninvolved skin (P < 0.0001; P = 0.002). Cellular adhesion molecules (CAMs) reached their highest expression at 30' and 60' in induced lesions, and they showed strong expression also in unaffected skin (ICAM-1: P < 0.0001). Our data show that the immunoinflammatory features of ASST-induced wheals involve a prevalent role of lymphocytes (with a mixed Th1/Th2 response), with strong neutrophil infiltration and activity and involvement of the chemokine pathway. We interpreted the finding of inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status".
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PMID:Chronic idiopathic urticaria: infiltrating cells and related cytokines in autologous serum-induced wheals. 1572 39

Tryptase has been suggested to take part in the pathophysiology of psoriasis mainly through the production of C3a by cleaving C3. However, studies using tryptase preparations of high purity do not support this notion. Therefore, although tryptase is unanimously believed to be involved in the immunopathogenesis of psoriasis, no convincing mechanism has been proposed for its role. This paper proposes several mechanisms by which this enyme may exert its role in the pathobiology of psoriasis. Tryptase is a mitogen for epithelial cells and stimulates IL-8 production and ICAM-1 expression by these cells. It also induces the expression of mRNA for IL-1beta and IL-8 and stimulates the selective release of IL-8 from endothelial cells and TNF-alpha, IL-1beta, and IL-6 from lymphocytes and monocytes. Besides itself being a chemoattractant for neutrophils, tryptase activates mast cells and generates kinins from kininogen, thereby playing a crucial role in leukocyte infiltration into psoriatic lesions. This enzyme also induces leukocyte infiltration partly through activating endothelial PAR-2, which contributes to leukocyte rolling, adherence and recruitment by inducing the release of endothelial platelet-activating factor. Through activating PAR-2, tryptase could also trigger the development of Langerhans cells which play a crucial role in the pathophysiology of psoriasis. This enzyme is a mitogen for fibroblasts, which are probably involved in the pathophysiology of psoriasis through production of insulin-like growth factor-I (IGF-I). Tryptase is a gelatinase and also activates stromelysin-1 (MMP-3), thereby contributing to the disruption of psoriatic basement membrane and to the joint damage seen in psoriatic arthritis. Increase of tryptase levels following trauma could also provide a mechanism for Koebner phenomenon seen in psoriasis.
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PMID:Possible molecular mechanisms to account for the involvement of tryptase in the pathogenesis of psoriasis. 1627 51


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