Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neutrophil enzyme elastase is a potent secretagogue of airway secretory cells, and elastase is present in high concentrations in sputum of patients with hypersecretion (e.g., cystic fibrosis, bronchiectasis). Interleukin-8 (IL-8), a recently discovered cytokine with potent neutrophil chemotactic properties in vitro, is also found in the sputum of these patients. We used an isolated tracheal segment in dogs in vivo to study the effect of IL-8 in causing neutrophil accumulation, elastase release, and secretion (by measuring lysozyme concentrations) in the luminal superfusate. IL-8 caused a potent time-dependent neutrophil accumulation at between 3 and 6 h. The effect was significant at 10(-9) and maximum at 10(-8) M. No increase in free elastase, cathepsin G, or lysozyme was detected in the superfusate. Thus, in contrast to previous studies showing that ragweed antigen causes the accumulation of neutrophil elastase which in turn causes lysozyme secretion, IL-8 causes neutrophil accumulation without granule secretion (or subsequent secretagogue activity). The findings were confirmed with dog and human neutrophils in vitro.
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PMID:Interleukin-8 induces neutrophil accumulation but not protease secretion in the canine trachea. 147 6

The human alveolar macrophage product, enzyme-releasing peptide (ERP), has a molecular mass of 8,000 Da, and releases azurophilic and specific granule constituents from neutrophils. A murine monoclonal anti-ERP antibody (12E10H), previously used to show a lack of antigenic identity between ERP and C5a, interleukin 1, tumor necrosis factor, and gamma-interferon, showed no cross-reactivity with interleukin 8. 12E10H and a fluorescein-labeled second antibody were used to visualize ERP on the macrophage surface. ERP was removed from alveolar macrophages by a 3-min incubation with 5 X 10(-7) M bovine pancreatic trypsin at 37 degrees C. The washed trypsinized cells could readhere to plastic and exclude trypan blue. Dilution of the trypsin-derived ERP released myeloperoxidase from cytochalasin-B-treated neutrophils dose dependently. The enzyme-releasing ability of the trypsin-derived material was removed by immunoprecipitation using antibody 12E10H bound to Staphylococcal protein A Sepharose 4B. The estimated molecular mass of the trypsin-derived ERP (by molecular sieve chromatography on HPLC) was approximately 8,500 Da. Other proteases (plasmin, thrombin, and cathepsin G) also released ERP from the cell surface, but the ERP was not an active secretagogue for neutrophils. However, macrophages cultured with protease inhibitors did not show decreased ERP accumulation in the medium. Our data indicate that ERP exists on the surface of human alveolar macrophages and can be released by proteases found within the lung environment in some disease states.
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PMID:Liberation of a neutrophil enzyme-releasing peptide from the surface of human alveolar macrophages. 236 Jun 46

We examined the effect of ulinastatin in comparison with prednisolone (PSL) and salazosulfapyridine (SASP), well-known drugs for ulcerative colitis (UC), on two experimental UC models induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNB) in rats. Ulinastatin at the doses of 3000 approximately 10,000 units/kg/day (i.v.) significantly ameliorated the formation of erosion and infiltration of inflammatory cells in colonic mucosa in DSS-induced rat UC models. Moreover, ulinastatin at the dose of 10,000 units/kg/day (i.v.) significantly suppressed inflammation with ulcer in the colonic mucosa in TNB-induced rat UC models. PSL at the dose of 1 mg/kg/day (p.o.) also was as effective as ulinastatin on the above two UC models, while SASP at the dose of 100 mg/kg/day (p.o.) was less effective than ulinastatin and PSL. In addition, ulinastatin inhibited the activities of elastase and cathepsin G from human leukocytes, and it suppressed TNF alpha, IL-8 and superoxide production by rat macrophages and rabbit leukocytes in vitro. These results suggest that the suppression of inflammatory mediators produced by leukocytes is involved in the mechanism of the anti-UC action of ulinastatin.
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PMID:[Effects of ulinastatin on experimental ulcerative colitis in rats]. 906 98

Biological activities of peptides representing two different regions in the TNF molecule were investigated. We have earlier reported that one of the peptides studied, TNF 36-62, induced chemotaxis in granulocytes and monocytes. TNF 41-62, a shorter analog of TNF 36-62, possessed similar chemotactic effects. Both peptides caused a weak enhancement of LPS -induced IL-6 production and tissue factor activity by monocytes in whole blood. The third peptide studied, TNF 78-96, was selected from a region located on the opposite side of the beta-sheet sandwich structure of the TNF molecule, and includes the loop 84-88 that has been shown to be involved in TNF receptor interaction. TNF 78-96 possessed properties quite different from TNF 36-62 and TNF 41-62. It amplified several fold PMA-induced secretion of elastase, and enhanced significantly PMA-induced secretion of cathepsin G from the neutrophils, activities which were effectively abolished by an anti-human TNF antibody. The TNF 78-96 peptide also inhibited LPS-induced TF activity in monocytes of whole blood, and it abolished the TNF enhancing effect of LPS-induced TF activity in a dose dependent manner. This suggests that the TNF 78-96 peptide may bind to the TNF receptor(s), without potentiating the same signals as native TNF. It may thereby prevent binding of the native TNF and the resultant activation effect of TNF. It also, at high concentrations, inhibited LPS-induced IL-6 production whereas it caused a doubling of LPS-induced IL-8 in monocytes and granulocytes in whole blood. These results clearly show that distinct TNF activities can be induced by peptide sequences taken from different regions of TNF. The TNF 78-96 peptide might be useful in downregulation of LPS-induced monocyte activations in vivo.
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PMID:TNF 41-62 and TNF 78-96 have distinct effects on LPS-induced tissue factor activity and the production of cytokines in human blood cells. 1078 Mar 24

The platelet-derived neutrophil-activating peptide 2 (NAP-2, 70 amino acids) belongs to the ELR(+) CXC subfamily of chemokines. Similar to other members of this group, such as IL-8, NAP-2 activates chemotaxis and degranulation in neutrophils (polymorphonuclear [PMN]) through chemokine receptors CXCR-1 and CXCR-2. However, platelets do not secrete NAP-2 as an active chemokine but as the C-terminal part of several precursors that lack PMN-stimulating capacity. As we have previously shown, PMN themselves may liberate NAP-2 from the precursor connective tissue-activating peptide III (CTAP-III, 85 amino acids) by proteolysis. Instead of inducing cell activation, continuous accumulation of the chemokine in the surroundings of the processing cells results in the down-regulation of specific surface-expressed NAP-2 binding sites and in the desensitization of chemokine-induced PMN degranulation. Thus, NAP-2 precursors may be regarded as indirect mediators of functional desensitization in neutrophils. In the current study we investigated the biologic impact of another major NAP-2 precursor, the platelet basic protein (PBP, 94 amino acids). We show that PBP is considerably more potent than CTAP-III to desensitize degranulation and chemotaxis in neutrophils. We present data suggesting that the high desensitizing capacity of PBP is based on its enhanced proteolytic cleavage into NAP-2 by neutrophil-expressed cathepsin G and that it involves efficient down-regulation of surface-expressed CXCR-2 while CXCR-1 is hardly affected. Correspondingly, we found PBP and, less potently, CTAP-III to inhibit CXCR-2- but not CXCR-1- dependent chemotaxis of neutrophils toward NAP-2. Altogether our findings demonstrate that the anti-inflammatory capacity of NAP-2 is governed by the species of its precursors.
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PMID:Down-regulation of neutrophil functions by the ELR(+) CXC chemokine platelet basic protein. 1104 72

Mobilization of hematopoietic stem and progenitor cells from the bone marrow into the circulation by repetitive, daily stimulations with G-CSF alone, or in combination with cyclophosphamide, is increasingly used clinically; however, the mechanism is not fully understood. Moreover, following mobilization stem cells also home back to the bone marrow, suggesting that stem cell release/mobilization and homing are sequential events with physiological roles. Previously, a role for cytokines such as G-CSF and SCF, and adhesion molecules such as VLA-4 and P/E selectins, was determined for stem cell mobilization. Recent results using experimental animal models and samples from clinical mobilization protocols demonstrate major involvement of chemokines such as stromal derived factor-1 (SDF-1) and IL-8, as well as proteolytic enzymes such as elastase, cathepsin G, and various MMPs in the mobilization process. These results will be reviewed together with the central roles of SDF-1 and CXCR4 interactions in G-CSF or G-CSF in combination with cyclophosphamide-induced mobilization. Furthermore, the central role of this chemokine in stem cell homing to the bone marrow as well as retention of undifferentiated cells within this tissue will also be discussed.
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PMID:Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. 1222 88

Interleukin (IL)-6 transsignaling plays a pivotal role in the shift from neutrophil to monocyte recruitment at the inflammatory site. Release of neutrophil IL-6 receptor-alpha (IL-6Ralpha, CD126) in its soluble form is a key step of IL-6 transsignaling, however, its physiological inducers are poorly known. Here, we observed that the neutrophil chemoattractants IL-8, C5a complement fraction, platelet activating factor, leukotriene B4 and N-formyl-methionyl-leucyl-phenylalanine rapidly decreased IL-6Ralpha membrane expression and increased soluble IL-6Ralpha concentrations in the neutrophil supernatants, consistent with a shedding process. IL-6Ralpha shedding involved a TNF-alpha-converting enzyme-type metalloproteinase since it was partly decreased in the presence of a specific inhibitor, but not cathepsin G since PMSF or alpha1 antichymotrypsin had no effect. Neutrophil IL-6Ralpha shedding may be a common feature of neutrophilic infiltrates in various inflammatory situations, allowing IL-6 transsignaling, decreasing neutrophil infiltration and in the meantime favoring monocyte recruitment, thus the initiation of an immune response and subsequently the resolution of inflammation.
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PMID:Chemotactic agents induce IL-6Ralpha shedding from polymorphonuclear cells: involvement of a metalloproteinase of the TNF-alpha-converting enzyme (TACE) type. 1235 50

Protease-activated receptors (PARs) compose a family of G protein-coupled receptors activated by proteolysis with exposure of their tethered ligand. Recently, we reported that a neutrophil-derived serine proteinase, proteinase 3 (PR3), activated human oral epithelial cells through PAR-2. The present study examined whether other neutrophil serine proteinases, human leukocyte elastase (HLE), and cathepsin G (Cat G) activate nonepithelial cells, human gingival fibroblasts (HGF). HLE and Cat G as well as PR3 activated HGF to produce IL-8 and monocyte chemoattractant protein 1. Human oral epithelial cells but not HGF express mRNA and protein of secretory leukocyte protease inhibitor, an inhibitor of HLE and Cat G, and recombinant secretory leukocyte protease inhibitor clearly inhibited the activation of HGF induced by HLE and Cat G but not by PR3. HGF express PAR-1 and PAR-2 mRNA in the cells and the proteins on the cell surface. HLE and Cat G 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 HLE and Cat G. The production of cytokine induced by HLE and Cat G and the PAR-2 agonist peptide was completely abolished by inhibition of phospholipase C. These findings suggest that neutrophil serine proteinases have equal ability to activate human nonepithelial cells through PAR-2 to produce inflammatory cytokines and may control a number of inflammatory processes such as periodontitis.
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PMID:Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2. 2030 34

Lactoferrin (Lf) is a member of the transferrin family of iron-binding anti-bacterial proteins, present in most exocrine secretions, such as saliva, and plays an important role in mucosal defense. In this study, we identified small Lf peptides with Con A low-affinity in the parotid saliva of chronic periodontitis patients by Con A two-dimensional immunoelectrophoresis, Con A affinity chromatography and Western blotting using anti-human Lf polyclonal Ab. N-terminal amino acid sequencing of the four Con A low-affinity Lf peptides confirmed them to be fragments of intact Lf. The detection ratio of the proteinase 3 (PR3)-like activity was elevated in the parotid saliva of periodontitis patients and was associated with the severity of clinical symptoms. PR3 protein was also detected in the parotid saliva of periodontitis patients, and PR3, but not human leukocyte elastase and cathepsin G, degraded intact Lf. Con A low-affinity saliva Lf peptides showed no anti-bacterial activity against Escherichia coli, and had a reduced iron-chelating capacity. Con A low-affinity saliva Lf peptides, PR3-treated Lf preparation and two of four synthetic polypeptides induced the production of interleukin IL-6, monocyte chemoattractant protein-1 and IL-8, and the activation of NF-kappaB in human oral epithelial HSC-2 cells. Furthermore, concentrations of the Lf peptides in the parotid saliva of periodontitis patients were increased with a correlation to the severity of clinical symptoms. These results suggest that Lf in the parotid saliva of periodontitis patients was degraded into small peptides by the PR3-like activity with the capability to induce inflammatory mediators.
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PMID:Cleaved inflammatory lactoferrin peptides in parotid saliva of periodontitis patients. 1703 Mar 85

Thymic epithelial cells can produce many kinds of cytokines, and interleukin (IL)-6-producing thymic carcinoma cases have been reported. However, a cytokine-producing human thymic tumor cell line has not previously been established. In this paper, we report a novel, multiple inflammatory cytokine-productive cell line that was established from a patient with thymic carcinoma. This cell line, designated ThyL-6, positively expressed epithelial membrane antigen, cytokeratins, vimentin intermediate filament and CD5, although hematological markers were not present in the cells. Cytokine antibody array analysis showed that the cells secreted several cytokines including IL-1alpha, IL-6, IL-8, RANTES, soluble TNFalpha-receptor 1, VEGF and CTLA into the culture medium. The addition of ThyL-6-cultured supernatant supported the growth of human myeloma ILKM-3 cells, which require the presence of IL-6 in the culture medium for the maintenance of cell growth, suggesting that the secreted IL-6 from ThyL-6 cells was biologically active. Chromosome analysis demonstrated that ThyL-6 cells had complex karyotype anomalies, including der(16)t(1;16); the latter has been recognized in thymic squamous cell carcinoma and thymic sarcomatoid carcinoma cases, as well as in several other kinds of malignancies. Heterotransplantation of the cells into nude mice showed tumorigenesis with neutrophil infiltration and liquefactive necrosis. These findings suggest that ThyL-6 cells will provide us with a new experimental tool for investigating not only the pathogenesis, biological behavior, chromo-somal analysis and therapeutic reagents of human thymic carcinoma, but also for studying cytokine-chemokine network systems.
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PMID:Multiple inflammatory cytokine-productive ThyL-6 cell line established from a patient with thymic carcinoma. 1869 Dec 42


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