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)

Neutrophil elastase (NE) is known to be one of the most potent proteases capable of deforming and detaching human bronchial epithelial cells (BECs) and inducing IL-8 gene expression. However, mechanisms of NE-induced IL-8 gene expression are unclear, especially with respect to how they relate to cellular detachment. To elucidate these mechanisms, effects of cell detachment and deformation following mechanical injury or pharmacologic stimuli on IL-8 gene expression were examined by Northern analyses. When BET-1A cells from a human bronchial epithelial cell line were incubated with NE (100 nM), trypsin (0.5 mg/ml), EGTA (7 mM), or EDTA (0.7 mM) to induce deformation and detachment, IL-8 mRNA transcript levels were up-regulated, as demonstrated in a case of mechanical detachment from the culture plate using a cell scraper. This IL-8 gene expression was inhibited by pretreatment with 5 microM taxol, a microtubule-stabilizing agent. Colchicine or vinblastine, microtubule-disrupting agents, induced IL-8 gene expression, which was also inhibited by taxol treatment. These data suggest that structural changes, including deformation of the cytoskeleton, especially microtubules, may contribute to IL-8 gene expression in human BECs. Since detachment and cellular deformation of BECs caused by proteases have been observed frequently in a variety of inflammatory airway diseases, our findings provide evidence that detached or deformed BECs potentially enhance production of inflammatory mediators in the pathogenesis of airway inflammation.
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PMID:Cellular detachment and deformation induce IL-8 gene expression in human bronchial epithelial cells. 854 32

Monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), RANTES, and macrophage inflammatory protein (MIP)-1 alpha are chemokines known to activate basophils (MCAF/RANTES) and eosinophils (RANTES/MIP-1 alpha). IL-8 inhibits MCAF-induced histamine release from basophils. We questioned whether a relationship exists between the levels of these chemokines and various inflammatory mediators released from mast cells, eosinophils, and basophils as assessed in nasal secretions obtained from patients during the allergy season and out of season. Samples were assessed for MCAF/MCP-1, RANTES, MIP-1 alpha, IL-8, histamine, tryptase and eosinophil cationic protein (ECP) in three subject groups: subjects with allergic rhinitis (n = 18), atopic subjects without rhinitis (n = 9), and healthy individuals (n = 6). Statistically significant differences were apparent only in the subjects with symptoms as follows. MCAF/MCP-1 increased during the season from 336 +/- 47 pg/ml to 829 +/- 137 pg/ml (p < 0.001), whereas IL-8 decreased from a baseline of 1932 +/- 335 pg/ml to 1070 +/- 202 pg/ml (p < 0.028). The ratio of IL-8 to MCAF/MCP-1 decreased during the symptomatic season from the baseline of 6.66 +/- 1.06 seen during winter to 1.3 +/- 0.22 during ragweed season (p < 0.001). Histamine increased from 6.3 +/- 1.5 to 89 +/- 15.5 ng/ml (p < 0.001), ECP increased from 20.6 +/- 6.4 to 237.1 +/- 50.2 ng/ml (p < 0.001), and tryptase increased from 2.34 +/- 0.6 to 9.7 +/- 2.3 U/ml (p < 0.001). Most samples did not have detectable quantities of MIP-1 alpha or RANTES. We also found a correlation between the level of MCAF/MCP-1 and IL-8 and the level of histamine or IL-8 and ECP. Our results suggest that the chemokines MCAF/MCP-1 and IL-8 may participate in the pathogenesis of allergic rhinitis, contributing to the attraction of the proinflammatory cells and mediator release, which might be very important during the late phase of the allergic reaction. Furthermore, the ratio of certain chemokines, such as MCAF/MCP-1 and IL-8 may reflect the magnitude of the reaction, as does the presence of histamine and ECP.
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PMID:Chemokines in seasonal allergic rhinitis. 856 22

Tryptase, a protease unique to the mast cell secretory granule, is released in substantial quantities into the respiratory tract of patients with inflammatory disease of the airways. We have investigated the potential of tryptase to act as a mitogen for bronchial epithelial cells and to stimulate release of IL-8 and expression of ICAM-1. Tryptase was isolated from extracts of human lung tissue using ammonium sulphate precipitation, octyl agarose, and heparin agarose chromatography. Purified tryptase stimulated DNA synthesis in the human epithelial cell line H292, as measured by [3H] thymidine incorporation. Maximal growth was observed after 24 h using 25 mU/ml of tryptase (where 1 micron is defined as that which can hydrolyze 1 mumol of the peptide substrate N-alpha-benzoyl-DL-arginine p-nitroanilide hydrochloride per minute at 25 degrees C), a concentration that is likely to be achieved in vivo. Inhibitors of tryptase activity, including leupeptin and benzamidine hydrochloride, significantly decreased tryptase-induced stimulation of DNA synthesis, indicating the requirement for an active catalytic site. Tryptase stimulated a catalytic site-dependent release of IL-8 from epithelial cells after 24 h, and this was associated with up-regulation of ICAM-1 expression, as revealed by FACS analysis. Tryptase may play a critical role in epithelial repair and in the recruitment of granulocytes following mast cell activation.
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PMID:Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. 859 74

We have applied the technique of sputum induction by hypertonic saline in asthmatics and nonatopic control subjects to study an array of indices of airway inflammation believed to be relevant to asthma pathogenesis. Compatible with a central role for eosinophils and mast cells in asthma, sputum of asthmatic subjects contained increased numbers of eosinophils and levels of eosinophil cationic protein (ECP) and mast cell tryptase. Eosinophil numbers, and ECP and histamine levels correlated with the degree of methacholine airways responsiveness, and ECP, tryptase, and histamine correlated with raised concentrations of albumin. Using the micro-Boyden chamber technique eosinophil chemotactic activity was identified only in the sputum from asthmatics. The correlation between the raised levels of total IgA, IL-8/IgA complexes, and tryptase and the degree of sputum eosinophilia and ECP levels, suggests possible mechanisms for eosinophil chemotaxis and activation in asthma. Row cytometric analysis of sputum lymphocytes showed an increase in CD4+ T cells and T cells expressing intercellular adhesion molecule-1 (ICAM-1) in asthma which, together with the finding of raised levels of soluble ICAM-1 in the sputum, indicates upregulation of this adhesion molecule. Finally, the proportion of CD16+ natural killer (NK) cells was reduced in the sputum of asthmatics. These observations highlight the importance of the airway inflammation in causing asthma and further confirm the usefulness of sputum induction as a tool in asthma research.
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PMID:Cell infiltration, ICAM-1 expression, and eosinophil chemotactic activity in asthmatic sputum. 903 80

We studied the effects of serine proteases on cytokine gene expression by cultured normal human keratinocytes. In resting keratinocytes, steady-state mRNA levels for interleukins IL-1 alpha, IL-1 beta, IL-7, and IL-8, transforming growth factors alpha and beta, and tumor necrosis alpha were sufficient to be detected by our reverse transcriptase-polymerase clozin reaction method. Incubation of keratinocytes with 25 nM trypsin or 1 unit/ml thrombin for 24 hr selectively upregulated mRNA levels for granulocyte-macrophage colony-stimulating factor (GM-CSF) and Il-6 to detectable levels. Keratinocytes secreted GM-CSF and IL-6 protein in response to these proteases. Monensin did not inhibit the gene expression for the cytokines, thereby excluding the possibility of intervention by secreted molecules. Aprotinin and argatroban inhibited the effects of the proteases. SFLLRN and SLIGRL, tethered ligand receptor peptides for thrombin receptor and for proteinase-activated receptor 2 (PAR-2), respectively, duplicated the effects of the proteases on keratinocytes, which expressed mRNA for both receptors. Trypsin increased tyrosine phosphorylated proteins and intracellular free calcium concentrations. Tyrphostin, pertussis toxin, or H-7 suppressed trypsin- and thrombin-induced GM-CSF gene expression. Our results demonstrate that the serine proteases activate thrombin receptors and PAR-2 on keratinocytes, triggering intracellular signaling and then inducing the synthesis of GM-CSF. We speculate that serine proteases modulate the course of physiological and pathological processes in the skin by stimulating keratinocytes to produce the cytokines.
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PMID:Thrombin and trypsin induce granulocyte-macrophage colony-stimulating factor and interleukin-6 gene expression in cultured normal human keratinocytes. 906 88

In the last decade, new information was achieved on mast cells (MC). Their origin is assumed to be different from that of the basophils. There are two types of MC with differences in structure, distribution and function: conjunctival and mucosal. MCs are among the most important cells in the development of allergic inflammation through the cytokines and mediators released on the activation of the surface receptors (high-affinity receptors for IgE: Fc epsilon R1). The cytokines released by MCs, e.g., interleukin 5 (IL5), IL8, are chemoattractants for eosinophils and neutrophils, respectively. The two types of mediators released by MC-those preformed, such as histamine, tryptase, serotonin, and the newly-synthetized ones, such as prostaglandin D2 (PGD2), leukotrienes C4 (LTD4), D4 (LTD4), E4 (LTE4), induce vasodilatation, bronchoconstriction, cellular chemotaxis, increase vascular permeability. The involvement of MC in many human diseases was shown within in vivo and in vitro studies (in allergy, lung fibrosis, atherosclerosis, carcinogenesis, etc.).
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PMID:Mast cells as potent inflammatory cells. 916 16

The currently available respiratory topical corticosteroids are all effective at reducing the nasal symptoms of itch, sneezing, rhinorrhoea and obstruction associated with allergic rhinitis. The mechanism of action of corticosteroids is related to their anti-inflammatory activities. They have been documented to prevent fluid exudation and reduce the number of circulating inflammatory cells, including lymphocytes, mast cells, basophils, eosinophils, macrophages, and neutrophils. This occurs through multiple mechanisms, e.g. eosinophil infiltration is suppressed by preventing cytokine production, reducing local mechanisms of tissue infiltration, and decreasing eosinophil survival. Furthermore, corticosteroids also reduce preformed and newly-generated mediators (e.g. histamine, tryptase, prostanoids, leukotrienes), and inhibit production of cytokines and chemokines by inflammatory cells (e.g. IL-1 through IL-6, IL-8, RANTES, TNF-alpha, IFN-gamma and GM-CSF). The currently available corticosteroids differ pharmacologically. Fluticasone propionate appears to have the greatest affinity for the glucocorticoid receptor, and binds more quickly and dissociates more slowly from the receptor compared with other corticosteroids, suggesting a more prolonged duration of action. Its increased specificity for respiratory tissue may lead to greater potency with less potential for systemic adverse effects. Fluticasone propionate has been compared with other corticosteroids in animal models for relative topical and systemic potency, and according to these data, it has the most favourable risk-benefit ratio.
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PMID:The pharmacological basis for the treatment of perennial allergic rhinitis and non-allergic rhinitis with topical corticosteroids. 921 61

The gastric mucosa of normal rats exhibits no detectable inflammation or visible damage. We examined the effect of the gastric mucosal extract of rats on neutrophil chemotaxis and tried to purify antichemotactic factor. The chemotaxis of neutrophils was examined by the modified Boyden's method. After mucosal layer was scraped and then homogenized and centrifuged at 20,000 x g for 30 min, the supernatant was used as rat gastric mucosal extract (RGME). Prior exposure of neutrophils to the gastric mucosal extract caused a dose-dependent reduction in the neutrophil migration induced by formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4) and interleukin 8 (IL-8) without affecting the cell viability. The antichemotactic factor was partially purified by lectin affinity chromatography on wheat germ lectin (WGL)-Sepharose, anion exchange chromatography on Mono-Q and gel filtration on Superose 12. The molecular weight of the antichemotactic factor was estimated to be around 60 k by gel filtration. The activity was markedly abolished by boiling for 5 min, heating at 60 degrees C for 30 min, and treatment with 1% acetic acid, 0.1 M Na2CO3 or trypsin. Furthermore, the FMLP-induced migration of neutrophils pretreated with the antichemotactic factor for 5 min followed by washing with fresh medium was inhibited, although the factor was not added to the chamber. These results suggest that the gastric mucosa of rats intrinsically generates an antichemotactic factor which might play a crucial role in maintenance of the integrity of the gastric mucosa.
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PMID:Characterization of antichemotactic factor extracted from the gastric mucosa of rats. 944 23

Recombinant mouse mast cell protease 6 (mMCP-6) was generated to study the role of this tryptase in inflammatory reactions. Seven to forty-eight hours after the i.p. injection of recombinant mMCP-6 into BALB/c, mast cell-deficient WCB6F1-Sl/Sl(d), C5-deficient, or mMCP-5-null mice, the number of neutrophils in the peritoneal cavity of each animal increased significantly by >50-fold. The failure of the closely related recombinant tryptase mMCP-7 to induce a comparable peritonitis indicates that the substrate specificities of the two tryptases are very different. Unlike most forms of acute inflammation, the mMCP-6-mediated peritonitis was relatively long lasting and neutrophil specific. Mouse MCP-6 did not induce neutrophil chemotaxis directly in an in vitro assay, but did promote chemotaxis of the leukocyte in the presence of endothelial cells. Mouse MCP-6 did not induce cultured human endothelial cells to express TNF-alpha, RANTES, IL-1alpha, or IL-6. However, the tryptase induced endothelial cells to express large amounts of IL-8 continually over a 40-h period. Neither enzymatically active mMCP-7 nor enzymatically inactive pro-mMCP-6 was able to induce endothelial cells to increase their expression of IL-8. Although the mechanism by which mMCP-6 induces neutrophil accumulation in tissues remains to be determined, the finding that mMCP-6 induces cultured human endothelial cells to selectively release large amounts of IL-8 raises the possibility that this tryptase regulates the steady state levels of neutrophil-specific chemokines in vivo during mast cell-mediated inflammatory events.
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PMID:Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6. 946 53

CD43 has been shown to be involved in the regulation of cellular adhesion and activation of leukocytes, but its functional significance for mast cell biology has been poorly defined. We demonstrate here that mAb engagement of surface CD43 on human leukemic (HMC-1) mast cells initiates a signaling cascade which involves protein kinase C, while tyrosine kinases appear to play a minor role, as evidenced by effects of different kinase inhibitors on homotypic aggregation induced via CD43. Furthermore, administration of an activating anti-CD43 mAb is shown to induce and promote TNF-alpha- and to enhance IL-8-secretion from HMC-1 cells, but it does not initiate histamine, tryptase, or LTC4 release, suggesting that the intracellular pathways leading to aggregation and release of certain mast cell mediators are differentially regulated. Additionally, engagement of CD43 on HMC-1 cells leads to down-regulation of CD43 surface expression, implying that CD43 may be potentially involved in its own regulation.
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PMID:Signal transduction via CD43 (leukosialin, sialophorin) and associated biological effects in human mast cell line (HMC-1). 947 99


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