UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated recently that methotrexate (MTX) inhibits superoxide generation and chemotaxis induced by N-formylmethionyl-leucyl-phenylalanine (fMLP) in neutrophils primed by granulocyte colony-stimulating factor (G-CSF). To extend these observations, we examined the in vitro effect of MTX on fMLP-stimulated superoxide generation and chemotaxis in neutrophils primed by either tumor necrosis factor alpha (TNF-alpha) or bacterial lipopolysaccharide (LPS). MTX inhibited superoxide generation and chemotaxis more efficiently in TNF-alpha- or LPS-primed neutrophils than in unprimed neutrophils. When either hypoxanthine or guanosine was added to the culture medium, the effects of MTX were partially counteracted. Furthermore, MTX caused a significant inhibition of both superoxide production induced by phorbol 12-myristate-13-acetate and chemotaxis induced by interleukin 8 in G-CSF-primed neutrophils. These results may support the hypothesis that neutrophils primed by different stimuli are more susceptible to the inhibitory effects of MTX on superoxide generation and chemotaxis irrespective of chemoattractants. Such an effect can be partly attributed to the perturbation of purine nucleotide biosynthesis.
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PMID:Inhibition of superoxide production and chemotaxis by methotrexate in neutrophils primed by TNF-alpha or LPS. 931 Jan 21

Activation of the serine/threonine kinase Akt, also called protein kinase B (PKB), was investigated in human neutrophils. Stimulation of the cells with the chemoattractant fMet-Leu-Phe or the chemokines IL-8 and GROalpha leads to the rapid and transient activation of PKB. Maximum PKB activation correlates with the well documented kinetics of respiratory burst and exocytosis. Wortmannin, a selective inhibitor of phosphoinositide 3-kinases (PI 3-kinases) in neutrophils, abrogates PKB activation. Similarly homo and heterotypic cross-linking of FcgammaIIA and FcgammaIIIB causes a transient activation of PKB that is sensitive to wortmannin treatment. Kinase activity measurements in immunoprecipitates from lysates of the myelocytic GM-1 cells or GM-1/CXCR1 cells, which are transfected with the IL-8 receptor 1, confirmed the transient activation of PKB observed in neutrophils. Stimulation of human monocytes with the CC chemokine RANTES (regulated on activation normal T cell expressed and secreted) also results in the activation of PKB. Preincubation of monocytes and neutrophils with Bordetella pertussis toxin inhibits fMet-Leu-Phe and RANTES-stimulated PKB activation, demonstrating that coupling of the receptors to heterotrimeric Gi-protein is required. The data show, that activation of PKB by Gi-protein-coupled receptors is mediated by PI 3-kinase and suggest that PKB is a constituent of neutrophil activating pathways.
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PMID:G-Protein-coupled receptors and Fcgamma-receptors mediate activation of Akt/protein kinase B in human phagocytes. 934 64

Chemotaxis of guinea pig eosinophils induced by various stimuli in use of a modified Boyden chamber technique in vitro and the effect of a platelet-activating factor (PAF) antagonist, apafant (CAS 105219-56-5, WEB 2086 BS), on it were examined. The eosinophils were obtained by bronchoalveolar lavage from the animals treated by i.v. injection with Sephadex G-200 and purified by Percoll density gradient centrifugation. PAF significantly and potently induced the chemotaxis at a broad range of 10(-17) to 10(-7) mol/l, where no concentration-dependency was observed. Leukotriene B4 also induced the chemotaxis in a concentration-dependent manner at 10(-14) to 10(-12) mol/l and the enhanced migration was not declined until 10(-7) mol/l. Interleukin-5 (IL-5), IL-8 and regulated on activation normal T expressed and secreted (RANTES) only modestly enhanced the chemotaxis in some concentrations at 10(-13) to 10(-7) mol/l with or without significance and with no concentration-dependency while formyl-methionyl-leucyl-phenylalanine (FMLP), a known chemoattractant, increased the migration at 10(-7) to 10(-5) mol/l. Apafant at 10(-8) to 10(-6) mol/l strongly and concentration-dependently inhibited 10(-8) mol/l PAF-induced chemotaxis. However, the drug showed nominal or no influences on their chemotaxis stimulated by the other agonists, at the concentrations of which the enhanced migration was observed. From these results, it is concluded that IL-5, IL-8 and RANTES, different from PAF and LTB4, are not potent stimuli for the eosinophil chemotaxis and that apafant is a selective antagonist of PAF, which is expected to be therapeutically effective for PAF-associated diseases including bronchial asthma.
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PMID:Eosinophil chemotaxis induced by several biologically active substances and the effects of apafant on it in vitro. 936 4

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

Recent identification of eosinophils as a cellular source of various cytokines suggests that eosinophil-derived cytokines contribute to allergic inflammation through either an autocrine or a paracrine fashion. The profound inhibitory effects of glucocorticoids (GCCs) on the production of various cytokines have been well recognized, however, there has been no definitive evidence that GCCs in fact inhibit cytokine generation by eosinophils. To verify the inhibitory ability of GCCs on eosinophil cytokine generation, we studied the effect of GCCs by determination of IL-8 and monocyte chemoattractant protein-1 (MCP-1) as parameters. Dexamethasone (DEX) inhibited both generation and secretion of IL-8 in a dose-dependent fashion. DEX also dampened formyl-methionyl-leucyl-phenylalanine-or ionomycin-induced eosinophil IL-8 production. Furthermore, MCP-1 production was also inhibited by DEX. The slope and the shape of the dose-response curve of DEX were similar irrespective of either the input stimuli or the output cytokines; half-maximal inhibition was observed at 10(-8) mol/L, and nearly complete abolishment was observed at 10(-7) mol/L. The competitive polymerase chain reaction for IL-8 mRNA and semiquantitative polymerase chain reaction for MCP-1 mRNA revealed that the inhibition occurred at a level of pretranslation. These results indicate that the beneficial effect of GCCs in allergic inflammation might be related, at least in part, to a direct effect of the drugs on eosinophil cytokine synthesis.
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PMID:Glucocorticoids inhibit chemokine generation by human eosinophils. 944 4

The neutrophil-dominated inflammation of the lung in cystic fibrosis (CF) has traditionally been seen as a physiological response to continuous opportunistic infection. Recent studies suggest, however, that regulation of the inflammatory response itself may be altered in CF. Neutrophil migration from the bloodstream involves alterations in surface expression of the adhesion molecules L-selectin and Mac-1 (CD11b/CD18). The aim of this study was to assess neutrophil adhesion molecule expression and responsiveness in CF. Neutrophils from chronic (n = 16) and acutely infected (n = 13) CF patients and 15 normal control subjects were directly assessed by Fluorescence-activated cell sorter (FACS) analysis for surface expression of L-selectin and CD11b before and after stimulation with interleukin 8 (IL-8) or f-Met-Leu-Phe (fMLP). Neutrophils from stable (n = 5) and acutely infected (n = 5) non-CF bronchiectasis patients were also assessed. Surface upregulation of CD11b was similar in all groups. Basal levels of L-selectin were also comparable among all groups, however, when stimulated, neutrophils from both stable and acutely infected CF patients shed significantly less L-selectin than those from control subjects (p < 0.05 and p < 0.01, respectively). This decreased responsiveness was not observed in either stable or acutely infected non-CF bronchiectasis patients. These results add to the accumulating evidence suggestive of a defective inflammatory response in CF.
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PMID:Neutrophil adhesion molecule surface expression and responsiveness in cystic fibrosis. 951 87

Interleukin-15 (IL-15) is a recently discovered cytokine produced by a wide range of different cell types including fibroblasts, keratinocytes, endothelial cells, and macrophages in response to lipopolysaccharide or microbial infection. This suggests that IL-15 may play a crucial role in the activation of phagocytic cells against pathogens. We studied polymorphonuclear leukocyte (PMN) activation by IL-15, evaluated as enhancement of PMN anti-Candida activity as well as IL-8 production, following stimulation with the cytokine. The PMN response to IL-15 depends on binding to the IL-15 receptor. Our experiments show that binding of a biotinylated human IL-15-immunoglobulin G2b IgG2b fusion protein was competed by the addition of human recombinant IL-15 (rIL-15) or of human rIL-2, suggesting that IL-15 binding to PMN might involve the IL-2Rbeta and IL-2Rgamma chains, which have been shown to be constitutively expressed by PMN. In addition, we show by reverse transcription-PCR and by flow cytometry with a specific anti-IL-15Ralpha chain monoclonal antibody that PMN express the IL-15Ralpha chain at the mRNA and protein levels. Incubation with IL-15 activated PMN to secrete the chemotactic factor IL-8, and the amount secreted was increased by costimulation with heat-inactivated Candida albicans. In addition, IL-15 primed the metabolic burst of PMN in response to formyl-methionyl-leucyl-phenylalanine but was not sufficient to trigger the respiratory burst or to increase the production of superoxide in PMN exposed to C. albicans. IL-15 also increased the ability of PMN to phagocytose heat-killed C. albicans organisms in a dose-dependent manner, without opsonization by antibodies or complement-derived products. In the same concentration range, IL-15 was as effective as gamma interferon (IFN-gamma) and IL-2 in increasing the C. albicans growth-inhibitory activity of PMN. Taken together, these results suggest that IL-15 is a potent stimulant of both proinflammatory and antifungal activities of PMN, activating several antimicrobial functions of PMN involved in the cellular response against C. albicans.
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PMID:Interleukin-15 activates proinflammatory and antimicrobial functions in polymorphonuclear cells. 959 28

Polymorphonuclear leukocyte (PMN) superoxide (.O2-) production has been implicated in the pathogenesis of cardiopulmonary bypass (CPB)-related end organ injury. PMN "priming" has been described as an event which enhances the release of .O2- following a second, activating insult. We hypothesized that PMN priming occurs during CBP and is temporally related to the plasma level of complement (C3a), interleukin (IL)-6, and IL-8. PMNs were isolated from 10 CPB patients pre-bypass (preCPB), 5 min after protamine administration (PROT), and at 6 and 24 h post-CPB. PMN .O2- production was measured by a cytochrome c reduction assay in the presence or absence of either phorbol 12-myristate-13-acetate (PMA, 0.4 microgram/ml) or N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 microM) and also after priming with 2000 nM platelet-activating factor (PAF) followed by activation with either PMA or FMLP. Plasma levels of C3a, IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. PMA-activated PMN .O2- production was significantly elevated at 6 h post-CPB compared to pre-CPB levels (11.04 +/- 0.9 vs 7.62 +/- 0.57, P = 0.009), indicating that CPB is associated with in vivo PMN priming. When PMNs were primed in vitro with PAF and then activated with PMA or FMLP, .O2- release at 6 h post-CPB was also significantly greater than pre-CPB levels (16.04 +/- 0.74 vs 12.2 +/- 0.92, P = 0.038; and 17.33 +/- 1.38 vs 13.33 +/- 1.35, P < 0.05), indicating that CPB acts synergistically with PAF to prime PMNs. Levels of C3a rose significantly over pre-CPB levels at PROT (P = 0.001), and IL-6 and IL-8 rose over pre-CPB levels at 6 h post-CPB (P = 0.01 and P = 0.006, respectively). These findings demonstrate that CPB not only directly primes PMNs, but also potentiates priming of PMNs by PAF. This "primed" PMN state, which coincided with the increased plasma levels of inflammatory mediators, may suggest a mechanism of predisposition to organ dysfunction following CPB.
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PMID:Cardiopulmonary bypass primes polymorphonuclear leukocytes. 965 92

Neutrophils isolated from patients with chronic bronchitis and emphysema have been shown to have enhanced responses to formyl peptides when assessed in vitro compared to age, sex matched controls. It is currently unclear whether the observed differences are due to a 'priming' effect by a second agent in vivo, or whether this is a primary difference in the neutrophils. We have studied the effects of interleukin-8, which is thought to be one of the major pro-inflammatory cytokines in chronic lung disease and granulocyte macrophage colony stimulating factor (GMCSF), in order to assess their effects on neutrophil chemotaxis and connective tissue degradation. In addition, we have assessed the effect of preincubation of these agents with neutrophils for 30 min followed by stimulation with F-Met-Leu-Phe (FMLP) to investigate any possible 'priming' effect that may be relevant to our clinical data. We report suppression of neutrophil chemotaxis to FMLP following incubation of the neutrophils with both IL-8 and GMCSF. However, we have observed an additive effect of IL-8 and FMLP for neutrophil degranulation leading to fibronectin degradation. The results suggest that IL-8 does not 'prime' neutrophils for subsequent FMLP stimulation as observed in vivo. Although the results for GMCSF were similar for the chemotactic response, the agent also had a synergistic effect on connective tissue degradation. However, it is concluded that neither agent could explain the enhanced neutrophil responses seen in our patients.
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PMID:The effect of interleukin-8 and granulocyte macrophage colony stimulating factor on the response of neutrophils to formyl methionyl leucyl phenylalanine. 968 20

We examined the effect of the neutrophil chemoattractants interleukin (IL)-8 and N-formyl-methionyl-leucyl-phenylalanine on goblet cell (GC) degranulation in guinea pigs. Chemoattractants caused time-dependent neutrophil recruitment and GC degranulation in vivo. NPC 15669 (an inhibitor of leukocyte infiltration) prevented both responses, implicating neutrophils. ICI 200,355 (an inhibitor of neutrophil elastase and proteinase-3) or secretory leukocyte protease inhibitor (an inhibitor of elastase but not of proteinase-3) abolished IL-8-induced GC degranulation, implicating elastase. Incubating tracheal segments with IL-8 plus neutrophils caused GC degranulation in vitro, an effect due to activation of the neutrophils themselves (and not an effect present in the supernatant). Chemoattractant increased surface staining of elastase and the cleavage of elastase-specific fluorogenic substrate by neutrophils. Pretreatment with anti-intercellular adhesion molecule-1, anti-CD18, or anti-CD11b antibody inhibited the chemoattractant-induced GC degranulation in vitro, implicating adhesion molecules. These studies suggest that chemoattractants cause neutrophil-dependent GC degranulation involving adhesive interactions between cells, with elastase activity occurring at the cell interface, causing GC secretion. The findings, reproduced in human airways, suggest novel methods of therapeutic intervention.
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PMID:Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules. 970 90

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