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

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

An inflammatory response has been observed in lung cancer both locally and systemically. The aim of the present study was to investigate whether the alveolar compartment was involved in the inflammatory response in non-small cell lung carcinoma (NSCLC). Both inflammatory mediators in bronchoalveolar lavage fluid (BALF) and cytokines produced by alveolar macrophages (AM) were investigated. Twenty patients with newly detected NSCLC and nine control subjects were studied. The patients had not been treated with chemotherapy, radiotherapy or with systemic or inhaled corticosteroids. All patients and control subjects were current smokers or stopped smoking recently. BAL was performed in the affected lung as well as in the contralateral lung of NSCLC patients, and only unilaterally in control subjects. Comparable results were demonstrated for the levels of the of the inflammatory mediators TNF-a, Interleukin (IL)-6, IL-8, both soluble TNF receptors and the soluble adhesion molecules E-selectin and intercellular adhesion molecule (ICAM)-1 between the affected lung and the contralateral lung in the NSCLC population as well as between the NSCLC population and the control subjects. Moreover, no significant differences in cytokine profiles of AM were found between AM obtained from the affected lung and from the contralateral lung. Although BAL is a useful tool in the diagnostic procedure for NSCLC, the present findings suggest that BAL does not reflect the enhanced inflammatory state, as reported in plasma and in the interstitial compartment around the tumour cells in NSCLC.
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PMID:The enhanced inflammatory response in non-small cell lung carcinoma is not reflected in the alveolar compartment. 951 29

Stimulation of human neutrophils with inflammatory mediators such as TNF-alpha or platelet-activating factor (PAF) induces translocation of adhesion molecule Mac-1 (CD11b/CD18) from secretory vesicles to the plasma membrane. Type II phospholipase A2 (PLA2-II) also induces translocation of Mac-1 from secretory vesicles. However, there are more Mac-1 molecules in gelatinase granules and specific granules than in secretory vesicles. Therefore, different combinations of PLA2-II and other mediators were examined for their ability to induce gelatinase granules and specific granules to induce Mac-1 surface expression. The combination of PLA2-II and PAF synergistically increased Mac-1 surface expression, and the effect was greater than the combinations of PLA2-II with TNF-alpha, IL-8, or FMLP. Additionally, the combination of PLA2-II and PAF induced exocytosis of both secretory vesicles and gelatinase granules, which did not occur with either PLA2-II alone or PAF alone. The induction was accompanied by marked production of leukotriene B4. AA861, an inhibitor of 5-lipoxygenase, did not inhibit exocytosis of secretory vesicles but did inhibit exocytosis of gelatinase granules and decrease Mac-1 surface expression. It was also found that Ca2+ influx is essential for 5-lipoxygenase activation, because Ni2+, which blocks the influx of extracellular Ca2+, inhibited the production of leukotriene B4. These results suggest that stimulation by the combination of PLA2-II and PAF, unlike stimulation by each mediator alone, causes exocytosis of gelatinase granules via the 5-lipoxygenase pathway, resulting in a synergistic increase in neutrophil Mac-1 surface expression during inflammatory processes.
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PMID:Synergistic effect of type II phospholipase A2 and platelet-activating factor on Mac-1 surface expression and exocytosis of gelatinase granules in human neutrophils: evidence for the 5-lipoxygenase-dependent mechanism. 959 Feb 57

Previously, we have shown that interleukin (IL)-8 induces the rapid (15 to 30 minutes) mobilization of hematopoietic progenitor cells (HPC) in mice. Because integrins are essential for adhesion and transendothelial migration of HPC, we studied the involvement of the beta2-integrin leukocyte function-associated antigen-1 (LFA-1) in IL-8-induced mobilization. After a single injection of blocking anti-LFA-1 antibodies, no mobilization of colony-forming cells was observed. In addition, when mice were pretreated with anti-LFA-1 or saline and subsequently injected with 30 microg of IL-8, mobilization of HPC was completely blocked. We showed that this was not due to anti-LFA-1 antibodies affecting colony formation, as addition of anti-LFA-1 antibodies to colony cultures in semisolid medium had no inhibitory activity. Also, anti-intercellular adhesion molecule (ICAM)-1 antibodies, directed to the main ligand of LFA-1 significantly inhibited the IL-8-induced mobilization. Furthermore, IL-1-induced mobilization was significantly inhibited by anti-LFA-1 antibodies. Because LFA-1 is reported to be expressed on more differentiated HPC, it was considered that the IL-8-induced mobilization of more primitive HPC would not be blocked by anti-LFA-1 antibodies. Transplantation of blood-derived mononuclear cells (MNC) from IL-8-mobilized animals pretreated with anti-LFA-1 antibodies protected only 25% of lethally irradiated recipient mice, whereas the radioprotection rate of control mice transplanted with MNC derived from IL-8-mobilized animals was 86% (P < .01). Anti-LFA-1 antibodies did not interfere with stem cell homing, as transplantation of IL-8-mobilized blood MNC, incubated in vitro with these antibodies resulted in 100% radioprotection. We conclude that anti-LFA-1 antibodies completely prevent the rapid mobilization of colony-forming cells and of cells with radioprotective capacity induced by IL-8. These results indicate a major role for the beta2-integrin LFA-1 in the IL-8-induced mobilization of hematopoietic stem cells.
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PMID:Anti-LFA-1 blocking antibodies prevent mobilization of hematopoietic progenitor cells induced by interleukin-8. 959 55

Our purpose was to determine the maximum tolerated dose and toxicity associated with soluble Chinese hamster ovary [s(CHO)] recombinant human interleukin (IL) 1 receptor (IL-1R; Immunex, Seattle, WA) administration in humans and to determine the effective biological dose and/or maximum tolerated dose of the s(CHO) IL-1R in combination with high-dose IL-2 as determined by reduction in IL-2 toxicity and modulation of its biological effects. Twenty-seven patients with metastatic cancer were treated with escalating doses of s(CHO) IL-1R at 1, 1, 5, 10, 20, 40, and 55 mg/m2 i.v. on days -6 (except cohort 2), 1, and 15 and IL-2 at doses of 300,000 IU/kg (cohort 1) and 600,000 IU/kg (cohorts 2-7) i.v. every 8 h on days 1-5 and 15-19. No toxicity directly attributable to s(CHO) IL-1R was observed. The median number of IL-2 doses was 23. Hypotension and neurotoxicity were the major dose-limiting toxicities for the IL-2/s(CHO) IL-1R combination. Of the 24 patients treated with full-dose IL-2, there were six responses, three complete and three partial (response rate, 25%). Three patients developed thyroid dysfunction, and all 3 responding melanoma patients exhibited vitiligo. The t1/2 of s(CHO) IL-1R alone was 24-30 h and was not significantly altered by coadministration with IL-2. Whole-blood functional assays indicated that sufficient s(CHO) IL-1R was present in the circulation at top dose levels to inhibit the in vitro effects of IL-1beta on IL-8 induction; however, no effect on IL-2-induced IL-8 induction, or on the IL-1beta- or IL-2-induced tumor necrosis factor production, was observed. Suppression of IL-2-mediated tumor necrosis factor alpha and IL-6 induction in vivo during the first 24 h after IL-2 administration was observed, and the neutrophil chemotactic defect normally seen with IL-2 was not observed. IL-1R antagonist induction far exceeded that seen previously with IL-2 alone. No inhibition of either serum C-reactive protein induction or enhanced urinary nitrate excretion and no consistent effect on IL-2-related changes in peripheral blood mononuclear cell phenotype or endothelial adhesion molecule expression were seen. The coadministration of s(CHO) IL-1R produced no apparent reduction in IL-2 clinical toxicity manifested by either the ability to administer more IL-2 than anticipated or a reduction in the toxicity associated with a given amount of IL-2. Therefore, no effective biological dose could be identified for the s(CHO) IL-1R.
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PMID:A two-part phase I trial of high-dose interleukin 2 in combination with soluble (Chinese hamster ovary) interleukin 1 receptor. 960 78

Cytokines are considered as mediators of immune and inflammatory responses. Cisternal CSF levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and of the soluble adhesion molecule E-selectin were evaluated in patients operated on for intracranial aneurysms. Cisternal CSF samples were obtained at surgery in 41 selected patients (31 with diagnosis of subarachnoid hemorrhage (SAH) and 10 control patients operated on for incidental unruptured aneurysms); 14 patients were operated within 72 h after SAH (early surgery) and 17 were operated after day 10 after the hemorrhage (delayed surgery). The CSF levels of cytokines were evaluated using radioimmunoassay and their concentrations were related to the timing of surgery, the amount of cisternal subarachnoid blood clots and the onset of clinical and angiographical evidence of arterial vasospasm. Mean cisternal CSF levels of IL-6, IL-8 and AMCP-1 are significantly higher in samples obtained from patients early operated after SAH, while levels of E-selectin were below the threshold value of the method in all 41 cases. In the early operated group 7 patients presented symptomatic vasospasm: levels of IL-8 and MCP-1 were not significantly different were compared to those of uncomplicated cases; on the other hand, significantly higher levels of IL-6 were shown in the subgroup of patients operated within 72 h after SAH and developing vasospasm. Among the patients undergoing delayed surgery 5 presented symptomatic vasospasm, but no significant difference was shown in cisternal CSF levels of cytokines measured. The results of the present study show that in patients with unruptured aneurysms cytokines are present in cisternal CSF in scarce quantities and that in subarachnoid spaces after SAH there is an impressive increase of IL-6, IL-8 and MCP-1. Moreover, the higher cisternal CSF levels of IL-6 found in the early stage after SAH might have a predictive value regarding the occurrence of symptomatic vasospasm.
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PMID:Cisternal CSF levels of cytokines after subarachnoid hemorrhage. 961 98

Human rhinoviruses (HRVs) are a frequent cause or upper respiratory tract infections in children and adults, and can exacerbate existing pulmonary disease. The major group of HRV attach to the receptor intercellular adhesion molecule (ICAM)-1, which is expressed on many cell types including epithelial cells. To study the influence of biological mediators on ICAM-1 expression, and consequently HRV attachment and infection, we have established an in vitro model system to evaluate the effects or pre-exposure to different cytokines on surface expression of ICAM-1 of uninfected and HRV-14-infected epithelial cells. The results of our studies show that the cytokines interleukin (IL)-1 beta, IL-8 and tumour necrosing factor (TNF)alpha increased ICAM-1 expression on epithelial cells. Epithelial cells infected with live HRV-14 displayed a significant upregulation of ICAM-1 compared to baseline. In contrast, interferon (IFN)gamma, whilst increasing the level of ICAM-1 expression on uninfected cells, induced a marked persistent downregulation of ICAM-1 expression on HRV-infected epithelial cells. In addition, IFN gamma appeared to completely override the ICAM-1 upregulation induced by IL-1 beta, IL-8 and TNF alpha, during HRV infection. We have further demonstrated that type 2 T-helper cell (Th2)-associated cytokines, predominantly IL-13, induce a marked upregulation or epithelial cell surface ICAM-1, thus increasing cellular binding sites for HRV attachment. As the airway mucosa or asthmatic subjects is predominantly infiltrated by activated type 2 T-helper cells with a simultaneous decrease of type 1 T-helper cells, our observations could explain the increased susceptibility to human rhinovirus infection observed in asthma.
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PMID:A biological model to explain the association between human rhinovirus respiratory infections and bronchial asthma. 963 14

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.
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PMID:Effects of 0.2 ppm ozone on biomarkers of inflammation in bronchoalveolar lavage fluid and bronchial mucosa of healthy subjects. 965 69

Keratinocytes are influenced by cytokines released by skin-infiltrating T lymphocytes. IL-17 is produced by activated CD4+ T cells and can stimulate epithelial cells. We investigated whether IL-17 could modulate the cytokine production and cell-surface molecule expression of keratinocytes. The effects of IL-17 were compared with those of IFN-gamma, which is also derived from activated T cells and is a strong stimulator for keratinocytes. IL-17 enhanced the mRNA and protein production of the proinflammatory cytokines IL-6 and IL-8 in a concentration-dependent way, and induced a weak expression of intercellular adhesion molecule (ICAM)-1 and HLA-DR. The production of IL-1alpha and IL-15 was not altered. IFN-gamma augmented the production of IL-6, IL-8, and IL-15 and strongly induced both cell-surface molecules. IL-17 and IFN-gamma showed marked synergism in the stimulation of IL-6 and IL-8 protein secretion and, to a lesser extent, in the induction of ICAM-1 and HLA-DR expression. The majority of the CD4+ and CD8+ T cell clones derived from lesional psoriatic skin expressed IL-17 mRNA, suggesting that skin-infiltrating T cells can produce this cytokine. This IL-17 mRNA expression was detectable in T helper cell type 1 and type 2 and did not correlate with the IFN-gamma or IL-4 production. In addition, IL-17 mRNA is detectable in biopsies from lesional psoriatic skin, but not in nonlesional control biopsies. Our study indicates that IL-17 is a proinflammatory cytokine, which could amplify the development of cutaneous inflammation and may support the maintenance of chronic dermatoses, through stimulation of keratinocytes to augment their secretion of proinflammatory cytokines.
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PMID:Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. 976 47

Heavy metal ions can be released by corroding metallic implants into the surrounding tissue. When they enter blood vessels some of them are carried by proteins like albumin and can be taken up by endothelial cells lining the vessels. To study their involvement in the inflammatory response we investigated heavy metal ion induced effects in cultured human vascular endothelial cells (HUVECs). NiCl2 and CoCl2 upregulate, especially in concentrations of 1 mM, the expression of adhesion molecules (e.g., E-selectin and intercellular adhesion molecule-1), as well as the cytokines IL-6 and IL-8, as shown by enzyme immunoassay and Northern blot analysis. In addition, possible signal transduction mechanisms were elucidated. The HUVECs were treated with various selective inhibitory drugs followed by the incubation of metal ions before measuring the expression of the above-mentioned endothelial factors. Two protein kinase inhibitors (H-7 and H-8) strongly repressed Ni2+ and Co2+ enhanced expression, as did the phospholipase A2 inhibitor quinacrine. Other selective inhibitors of protein kinases C or A, or cGMP-dependent protein kinases, as well as calcium antagonists like 1,2-bis(2-aminophenoxy)ethan-N,N,N',N'-tetraacetic acid and 3,4,5-trimethoxybenzosaure 8-(diethylamino)-octylester and inhibitors of receptor mediated endocytosis (primary amines), had no influence. We showed that NiCl2 and CoCl2 activate the translocation of the transcription factor nuclear factor (NF)-kappaB into the cell nucleus and enhance its binding to a NF-kappaB consensus sequence as shown by mobility shift analysis. Furthermore, we demonstrated the activation of AP-1. Despite the repression of heavy metal induced adhesion molecule synthesis, we did not detect any inhibition of NF-kappaB translocation by H-7 or H-8. Therefore, it must be concluded that heavy metal ions like Ni2+ and Co2+ activate two or more signal transduction pathways in endothelial cells. We clearly showed that there is one pathway in which H-7 and H-8 sensitive protein kinases are involved and a second pathway leading to NF-kappaB activation, which is insensitive to H-7 and H-8. Our results demonstrate that heavy metal ions induce mechanisms of gene activation in endothelial cells as do proinflammatory mediators, indicating that corroding metal ion containing biomaterials can provoke inflammatory reactions by known, as well as by yet unknown, intracellular signaling pathways.
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PMID:Mechanisms of cell activation by heavy metal ions. 1088 Jan


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