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)

Glutamine (Gln) supplementation has been shown to decrease production of pro-inflammatory cytokines by the human intestinal mucosa. The mechanism of this is poorly understood. We hypothesize that Gln down-regulates lipopolysaccharide (LPS)-stimulated pro-inflammatory cytokine production in Caco-2 cells by nuclear factor-kappa B (NF-kappaB). Caco-2 cells were incubated with different concentrations of Gln with or without methionine sulfoximine (MS, an inhibitor of glutamine synthetase) before stimulation with LPS. IL-6, IL-8, IL-10 and TNF-alpha protein and mRNA level were determined. NF-kappaB translocation was determined using an ELISA-based kit. IL-8 was the only detectable cytokine/chemokine. The largest amount of IL-8 was secreted by cells in the presence of MS with no Gln in the medium after exposure to LPS. LPS increased IL-8 production, peaking 10h after LPS administration. The addition of Gln (0.5 or 5.0mM) decreased IL-8 peptide and mRNA expression. LPS increased NF-kappaB nuclear translocation in the presence or absence of MS. Neither Gln nor MS altered NF-kappaB nuclear translocation. These results indicate that the lack of glutamine increases IL-8 production by Caco-2 cells after LPS stimulation. However, the glutamine-mediated decrease in LPS-stimulated IL-8 production is not associated with NF-kappaB p50 nuclear binding.
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PMID:Glutamine decreases lipopolysaccharide-induced IL-8 production in Caco-2 cells through a non-NF-kappaB p50 mechanism. 1284 6

Gram-negative enteric bacilli, such as Escherichia coli, are common causes of nosocomial pneumonia. The interaction between pulmonary neutrophils and the infecting pathogen is a critical step in determining the outcome. Previous studies from our laboratory, for which a rat model of pneumonia was used, established that pulmonary neutrophil recruitment was modulated by the E. coli virulence factors capsule and O-specific antigen. To begin to understand the mechanism by which this recruitment occurs, we conducted in vitro and ex vivo chemotaxis assays, for which we used a clinically relevant E. coli isolate (CP9) and isogenic derivatives that were deficient in only the O antigen (CP921) or capsule (CP9.137) as chemoattractants with or without the high-affinity N-formylmethionyl-leucyl-phenylalanine receptor antagonist N-tert-butoxycarbonyl-methionine-leucine-phenylalanine (N-t-BOC). Given that only live E. coli was used for the initial in vitro chemotaxis assays, it was predicted that only N-t-BOC-sensitive chemotaxis would occur. However, both N-t-BOC-sensitive and -insensitive chemotaxis was observed. N-t-BOC-insensitive chemotaxis was mediated in part by interleukin 8, which was produced by neutrophils that had migrated toward E. coli. N-t-BOC-insensitive chemotaxis was only observed when live E. coli bacteria, not cell-free E. coli culture supernatants, were used as chemoattractants, suggesting that a direct E. coli-neutrophil interaction was necessary. The presence of both capsule and O antigen diminished total, N-t-BOC-sensitive, and N-t-BOC-insensitive neutrophil chemotaxis in vitro. The presence of capsule significantly decreased total, N-t-BOC-sensitive, and N-t-BOC-insensitive neutrophil chemotaxis ex vivo when cell-free bronchoalveolar lavage fluid from infected rats was used as the source of chemotactic factors. These effects of E. coli capsule and O antigen on neutrophil chemotaxis are novel, and they expand our understanding of the mechanisms by which these virulence traits contribute to the pathogenesis of gram-negative pneumonia and other extraintestinal infections.
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PMID:Human neutrophil chemotaxis is modulated by capsule and O antigen from an extraintestinal pathogenic Escherichia coli strain. 1457 65

The mechanism of glutamine (Gln)-mediated down-regulation of inflammation in the intestine is poorly understood. We hypothesize that Gln down-regulates lipopolysaccharide (LPS)-stimulated IL-8 production in intestinal epithelial cells via transcription factors that counteract the effect of LPS-mediated increase in IL-8. Caco-2 cells were incubated with different doses of Gln with or without methionine sulfoximine (MS), an inhibitor of glutamine synthetase for 24 h before stimulation by LPS (100 microg/ml for 24 h). Inhibitors of the mitogen activated protein kinase (MAPK) family were added to cells for 1.5 h following stimulation by LPS. The p38 inhibitor SB 203580 resulted in a significant decrease in IL-8 peptide production (p < 0.01). However, p38 MAPK activity increased with Gln (p < 0.05), suggesting that this was not involved with Gln-mediated down-regulation of IL-8. Screening of 54 transcription factors demonstrated that STAT-4 was the only inflammation-related transcription factor that was up-regulated by Gln depletion and down-regulated with Gln supplementation (2-fold increase), paralleling IL-8 production. EMSA analysis confirmed these findings (3.5-fold increase). These results indicate that Gln deprivation enhances IL-8 production by Caco-2 cells after LPS stimulation and that down-regulation of IL-8 production with Gln is associated with alterations in STAT-4 transcription factor binding.
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PMID:Mechanism of glutamine-mediated amelioration of lipopolysaccharide-induced IL-8 production in Caco-2 cells. 1505 Jun 5

CP-64131 (CP), an aminobenzazepine with cytokine-like, physiologic effects similar to granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF, increases the number of neutrophils and stimulates marrow recovery after doxirubicin ablation. CP can also function as a neutrophil agonist, like formyl-Met-leu-Phe (fMLP). In these studies, we show that CP is unique in that it stimulates the p38-mitogen-activated protein kinase (MAPK) pathway but not extracellular signal-regulated kinase (ERK)1/2 or c-jun N-terminal kinase MAPKs in human neutrophils from peripheral blood. This is in contrast to other neutrophil agonists such as fMLP, interleukin (IL)-8, or GM-CSF, which stimulate multiple MAPK pathways. Like fMLP and IL-8, CP is capable of stimulating superoxide (O2-) production, CD11b expression, and cell polarization in human neutrophils. CP-stimulated O2- production is completely dependent on p38-MAPK activation, as determined by sensitivity to the p38-MAPK inhibitor SB203580. In contrast, SB203580 only partially inhibits expression of CD11b and has no effect on cell polarization stimulated by CP. Therefore, CP treatment of neutrophils activates p38-MAPK but has effects independent of p38-MAPK activation. In human embryonic kidney 293 cells, a human kidney epithelial cell line CP stimulates p38-MAPK and modestly activates ERK1/2. The findings define CP as a novel, small molecule, which has little cellular toxicity in vitro. CP has the ability to activate specific MAPK pathways in different cell types and should prove to be an effective agonist in combination with inhibitors to study biological responses regulated by MAPKs.
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PMID:CP-64131, an aminobenzazepine with cytokine-like properties, stimulates human neutrophil functions through the p38-MAPK pathway. 1515 76

Axenically grown Entamoeba histolytica produces a pentapeptide (Met-Gln-Cys-Asn-Ser) with anti-inflammatory properties that, among others, inhibits the in vitro and in vivo locomotion of human monocytes, sparing polymorphonuclear leucocytes from this effect [hence the name originally given. Monocyte Locomotion Inhibitory Factor (MLIF)]. A synthetic construct of this peptide displays the same effects as the native material. We now added MLIF to resting and PMA-stimulated cells of a human monocyte cell line and measured the effect upon mRNA and protein expression of pro-inflammatory chemokines (RANTES, IP-10, MIP-1alpha, MIP-1beta, MCP-1, IL-8, I-309 and lymphotactin) and the shared CC receptor repertoire. The constitutive expression of these chemokines and the CC receptors was unaffected, whereas induced expression of MIP-1alpha, MIP-1beta, and I-309, and that of the CCR1 receptor--all involved in monocyte chemotaxis--was significantly inhibited by MLIF. This suggests that the inhibition of monocyte functions by MLIF may not only be exerted directly on these cells, but also--and perhaps foremost--through a conglomerate down-regulation of endogenous pro-inflammatory chemokines.
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PMID:An anti-inflammatory oligopeptide produced by Entamoeba histolytica down-regulates the expression of pro-inflammatory chemokines. 1515 24

Delayed polymorphonuclear leukocyte (PMN) apoptosis exacerbates acute lung injury. To reach the alveolar spaces, PMNs must migrate across both pulmonary endothelial and epithelial cell layers. We hypothesized that transmigration across the endothelium-epithelium bilayer suppresses PMN apoptosis and sought to elucidate the underlying mechanisms. PMNs freshly isolated from normal volunteers were allowed to migrate across polycarbonate membranes alone or membranes coated with a bilayer of human lung endothelial and epithelial cells. After migration toward different chemoattractants (IL-8, formyl-Met-Leu-Phe, or leukotriene B(4)), PMN apoptosis and caspase activities were assessed by annexin V, histology, and enzymatic assays, respectively. Messenger RNA and specific protein expression in three receptor ligand-mediated, apoptosis-inducing pathways (Fas, TNF-alpha, and TNF-related apoptosis-inducing ligand) were further examined by gene array, RT-PCR, flow cytometry, and Western blot analyses. The data demonstrated that transbilayer migration suppressed PMN apoptosis, and this effect was not chemoattractant type specific. Kinetic analyses further showed that the delay of apoptosis was sustained to at least 18 h. Transbilayer migration caused significant decreases in caspase (-3, -8, and -9) activities. The changes in apoptosis-related gene expression support the survival role of transbilayer migration. Furthermore, the reduced apoptosis was correlated with downregulation of Fas ligand and TNF receptor 1 expression. Our data reveal that migration across a lung endothelium-epithelium bilayer suppresses PMN apoptosis. The decreased activity and/or expression of proapoptotic proteins may provide possible targets for the regulation of inappropriate delay in PMN apoptosis during lung inflammation and injury.
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PMID:Regulation of polymorphonuclear leukocyte apoptosis: role of lung endothelium-epithelium bilayer transmigration. 1547 82

Tumor necrosis factor-alpha (TNF-alpha)-induced signaling is pivotally involved in the pathogenesis of chronic inflammatory diseases. A polymorphism in the TNF receptor 2 (TNFR2) gene resulting in a juxtamembrane inversion from methionine (TNFR2(196MET)) to arginine (TNFR2(196ARG)) has been genetically associated with an increased risk for systemic lupus erythematosus and familial rheumatoid arthritis. Albeit the mutation does not affect the TNF binding kinetics of TNFR2, the present study provides evidence that the mutation results in a significantly lower capability to induce TNFR2-mediated NF-kappaB activation. Pretriggering of TNFR2 with a receptor-specific mutein leads to an enhancement of TNFR1-induced apoptosis, which is further increased in cells carrying the TNFR2(196ARG) variant. A diminished induction of NF-kappaB-dependent target genes conveying either anti-apoptotic or pro-inflammatory functions, such as cIAP1, TRAF1, IL-6, or IL-8 is observed. The mutated form TNFR2(196ARG) shows a reduction of inducible TRAF2 recruitment upon TNF-alpha stimulation. The findings suggest a common molecular mechanism for the involvement of the TNFR2(196ARG) variant in the etiopathogenesis of different chronic inflammatory disorders.
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PMID:The Met-196 -> Arg variation of human tumor necrosis factor receptor 2 (TNFR2) affects TNF-alpha-induced apoptosis by impaired NF-kappaB signaling and target gene expression. 1557 57

To investigate effects of supplementation of folic acid on the expression of adhesion molecules VCAM-1 in the aortas of rats with hyperhomocysteinemia. Thirty male SD rats (200 +/- 20 g) were invided into 3 groups (n = 10 for each group): control group(Control), high Met group(Met) and Met plus Folate group(Met + Folate), fed. for 45 days. Plasma Hcy levels were higher with the high-methionine diet (140.68 +/- 36.87 micromol/L vs 6.47 +/- 1.10 micromol/L in control rats) an effect which was reduced by folate. Respectively, the aortic expression of adhesion molecules VCAM-1 at protein and mRNA levels were higher in the Met groups than those in the control groups or the Met + Folate groups. A high methionine diet for 45 days was sufficient to induce hyperhomocysteinemia. Folate supplementation prevented elevation of Hcy levels in the blood, and reduced expression of the adhesion molecule VCAM-1. Hyperhomocysteinemia is now regarded as one of the important risk factors for cardiovascular and cerebralvascular disorders.[Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 38(15):1042-50.] Several plausible mechanisms for Hcy-induecd atherosclerosis have been proposed. These include endothelial dysfunction, enhancement of oxidative stress, reduction in NO bioavailability, and augmentation of thrombus formation.[Holven KB, Holm T, Aukrust P, et al. Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects . Am J Med 2001;110(7):536-42; Guba SC, Fonseca V, Fink LM. Hyperhomocysteinemia and thrombosis. Semin Thromb Hemost 1999;25(3):291-309.] However, the precise molecular mechanism is still unclear. Recent reports have suggested a role for inflammatory processes in the pathogenesis of atherosclerosis.[Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2(2):108-15.] Dysfunction of endothelial cells is the key process promoting inflammatory reactions. On injury, endothlial cells are capable of producing various cytokines that participate in inflammatory reactions in the arterial wall. Although results from in vitro studies suggest that Hcy, at pathophysiological concentrations, stimulates chemokine expression in vascular cells, it is unknown whether hyperhomocysteinemia can initiate similar changes, leading to enhanced momocyte adhesion/binding to the vascular endothelium in vivo.[Zeng X, Dai J, Remick DG, Wang X. Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes. Circ Res 2003;93(4):311-20.] On the basis of the potential pathogenic role of chemokines in atherogenesis, the objective of the present study was to investigate that homocsteine may exert its effect in part though adhesion molecules VCAM-1 and that folic acid supplementation may downregulate these inflammatory responses. Male Sprague-Dawley rats (bred from animal centers of Tongji Medical College, Huazhong Science and Technology University) aged 8 weeks were divided into 3 groups(n=10 for each group) and maintained for 45 days on the following diets before the experiments: (1) regular diet; (2) high-metheionine diet, consisting of regular diet plus 1.7% methionine; and (3) high-methionine plus folate -rich diet, consisting of regular diet plus 1.7% methionine and 0.006% folate.[Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res 2000;21(2-3):129-d37.] Plasma and serum samples wee colleced and stored at -80 degrees C after 45 days until analysis. The plasma homocysteine concentration of rats in three groups were determined by high-pressue liquid chromatography. To detect the endothelial expression of adhesion molecules VCAM-1, the thoracic aorta was isolated and dived into segments. These segments were immersion-fixed in 10% neutral-buffered formalin overlight and then embedded in paraffin. Sequential 5 mum paraffin-embedded cross sections were prepared. Immunohistochemical analyisis was performed to detect vascular cell adhesion molecule(VCAM)-1, The fixed cryosections were immediately blcked in 10% horse serum and phosphate baffered saline(PBS) at room temperature for 30 min. Goat polyclonal andibodies against rat VCAM-1(Santa Cruz Biotechnology) were diluted 1:100 in PBS and incubated with the cryosections for 1 h of room temperature. After three washes, the sections were incubated with biotin-conjugated rabbit anti-goat immunoglobulins(Dako) at 1:250 dilution in PBS. After three washes, the samples were mounted in 90% glycerol-PBS. Photographs were taken by use of a light microscope at a mignification of x200.
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PMID:Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia. 1618 51

Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-kappaB (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumor-produced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8.
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PMID:Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. 1632 49

Alcoholic liver disease (ALD) remains an important complication and cause of morbidity and mortality from alcohol abuse. Major developments in our understanding of the mechanisms of ALD over the past decade are now being translated into new forms of therapy for this disease process which currently has no FDA approved treatment. Cytokines are low molecular weight mediators of cellular communication, and the pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to play a pivotal role in the development of experimental ALD. Similarly, TNF levels are elevated in the serum of alcoholic hepatitis patients. Abnormal methionine metabolism is well documented in patients with ALD, with patients having elevated serum methionine levels, but low S-adenosylmethionine levels in the liver. On the other hand, S-adenosylhomocysteine and homocysteine levels are elevated in ALD. Recent studies have documented potential interactions between homocysteine and S-adenosylhomocysteine with TNF in the development of ALD. Altered proteasome function also is now well documented in ALD, and decreased proteasome function can cause hepatocyte apoptosis. Recently it has been shown that decreased proteasome function can also act synergistically to enhance TNF hepatotoxicity. Hepatocytes dying of proteasome dysfunction release pro-inflammatory cytokines such as Interleukin-8 to cause sustained inflammation. This article reviews the interactions of cytokines, altered methionine metabolism, and proteasome dysfunction in the development of ALD.
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PMID:Dysregulated cytokine metabolism, altered hepatic methionine metabolism and proteasome dysfunction in alcoholic liver disease. 1634 6


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