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)

Among leukocytes, only monocytes and macrophages were found to be highly susceptible to an infection by influenza A virus. After infection, de novo viral protein synthesis was initiated but then interrupted after 4-6 h. Most macrophages died by apoptosis within 25-30 h. Before cell death, however, macrophages responded to influenza A virus with a high cytokine gene transcription and subsequent release of tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, interferon (IFN)-alpha/beta, and CC-chemokines. The basic mechanisms of virus-induced cytokine expression are still unknown and appear to involve transcription factors such as nuclear factor-kappaB and AP-1 which, however, were only activated for 2 h and declined below control values thereafter. After influenza A virus infection, only the mononuclear cell attracting CC-chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES were produced while the prototype neutrophil CXC-chemoattractants IL-8 and GRO-alpha were entirely suppressed. This selective induction of CC-chemokines may explain the preferential influx of mononuclear leukocytes into virus-infected tissue. Our data show that monocytes and macrophages represent a primary target for an influenza A virus infection. Thus, the mononuclear phagocyte response leads to a rapid proinflammatory reaction and an enhanced immigration of mononuclear leukocytes, which may condition the infected host for the subsequent virus antigen-specific defense.
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PMID:Susceptibility of mononuclear phagocytes to influenza A virus infection and possible role in the antiviral response. 910 26

LPS-induced expression of the IL-8 gene was markedly enhanced by H2O2 or by deprivation of the cellular antioxidant glutathione by L-buthionine-(S,R)-sulfoximine (BSO) in human astrocytoma U373 cells. In contrast, it was markedly suppressed by the reductant N-acetyl-L-cysteine (NAC) and other antioxidants. Transient expression analysis using the chloramphenicol acetyltransferase assay revealed that activation of the IL-8 promoter by LPS was stimulated by BSO and was suppressed by NAC; likewise LPS-induced activation of both NF kappa B and AP-1 was enhanced by BSO and inhibited by NAC. These results suggest that LPS-induced IL-8 gene expression is regulated by cellular redox via modulation of these transcription factors.
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PMID:Redox regulation of lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) gene expression mediated by NF kappa B and AP-1 in human astrocytoma U373 cells. 912 24

Caprine arthritis encephalitis virus (CAEV) is a lentivirus of goats that leads to chronic mononuclear infiltration of various tissues, in particular, the radiocarpal joints. Cells of the monocyte/macrophage lineage are the major host cells of CAEV in vivo. We have shown that infection of cultured goat macrophages with CAEV results in an alteration of cytokine expression in vitro. Constitutive expression of interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) was increased in infected macrophages, whereas transforming growth factor beta1 (TGF-beta1) mRNA was down-regulated. When macrophages were infected with a CAEV clone lacking the trans-acting nuclear regulatory gene tat, IL-8 and MCP-1 were also increased. No significant differences from cells infected with the wild-type clone were observed, suggesting that Tat is not required for the increased expression of IL-8 and MCP-1 in infected macrophages. Furthermore, infection with CAEV led to an altered pattern of cytokine expression in response to lipopolysaccharide (LPS), heat-killed Listeria monocytogenes plus gamma interferon, or fixed cells of Staphylococcus aureus Cowan I. In infected macrophages, tumor necrosis factor alpha, IL-1beta, IL-6, and IL-12 p40 mRNA expression was reduced in response to all stimuli tested whereas changes in expression of granulocyte-macrophage colony-stimulating factor depended on the stimulating agent. Electrophoretic mobility shift assays demonstrated that, in contrast to effects of human immunodeficiency virus infection of macrophages, CAEV infection had no effect on the level of constitutive nuclear factor-kappaB (NF-kappaB) activity or on the level of LPS-stimulated NF-kappaB activity, suggesting that NF-kappaB is not involved in altered regulation of cytokine expression in CAEV-infected cells. In contrast, activator protein 1 (AP-1) binding activity was decreased in infected macrophages. These data show that CAEV infection may result in a dysregulation of expression of cytokines in macrophages. This finding suggests that CAEV may modulate the accessory functions of infected macrophages and the antiviral immune response in vivo.
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PMID:Caprine arthritis encephalitis virus dysregulates the expression of cytokines in macrophages. 931 28

We analyzed the influence of heavy-metal ions on human umbilical vein endothelial cells (HUVEC) in comparison to proinflammatory cytokines (TNF-alpha, IL-1beta) and lipopolysaccharide (LPS). Adhesion molecule and cytokine expressions are upregulated by heavy-metal exposure. Expression of E-selectin on the cell surface was strongly induced by 1-mM concentrations of NiCl2 and CoCl2, whereas ZnCl2 and CrCl3 had no influence. Furthermore, it is shown that NiCl2 induces mRNA expression of E-selectin, intercellular adhesion molecule-1, IL-6 and IL-8 in a 1-mM concentration. The transcription factor NF-kappaB is known to be involved in the regulation of adhesion molecule expression in endothelial cells after activation by proinflammatory cytokines. We demonstrated that treatment of HUVEC with Ni2+ and Co2+ ions induces the translocation of NF-kappaB p65 and also p50 into the nucleus. NF-kappaB binding activity is enhanced under the influence of heavy metals as determined by mobility shift analysis. P65 and p50 are components of the NF-kappaB complexes as confirmed by supershift analysis. We could show that activation at the protein level is accompanied by induction of NF-kappaB p65 mRNA expression. HUVEC also express the NF-kappaB inhibitor I kappaB-alpha (MAD-3). In the early phase of activation by Ni2+ and Co2+ ions, disappearance of I kappaB-alpha in the cytoplasm accompanied p65 translocation, followed by its gradual reappearence. Because I kappaB mRNA could be upregulated by NiCl2 as well as by a mixture of cytokines, we suggest that the replenishment of the inhibitor in the cytoplasm is caused by de novo I kappaB gene expression. In addition to the enhanced DNA-binding activity of NF-kappaB, another transcription factor, AP-1, was also augmented in HUVEC stimulated by NiCl2, CoCl2 or by proinflammatory mediators and the phorbol ester PMA. Fos protein is shown to be a component of the activated AP-1 complex, as determined by supershift analysis, suggesting that it consists of Jun/Fos heterodimers.
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PMID:Heavy metal ion induction of adhesion molecules and cytokines in human endothelial cells: the role of NF-kappaB, I kappaB-alpha and AP-1. 945 94

Inhibition of protein synthesis may result in superinduction of short-lived transcripts and has been attributed variably to stabilization of transcripts and/or increased gene transcription. Little is known about the kinetics of these processes and relevant transcriptional elements have not been identified. In this study, we describe superinduction of interleukin 8 (IL-8) mRNA, an important inflammatory mediator, in lung epithelial-like H292 cells and identify the underlying molecular mechanisms and their kinetics. Cycloheximide (CHI, 10 microg/ml), an inhibitor of protein synthesis, maximally increased IL-8 mRNA levels 30-fold in H292 cells. Tumour necrosis factor alpha (TNF-alpha), which induced IL-8 mRNA 3-fold, synergized with CHI causing a 150-fold increase at 6 h. CHI early on increased the stability of IL-8 mRNA (from 40 min in cells cultured with medium to more than 4 h with CHI). CHI also increased transcription as shown by transfection with IL-8 promoter constructs. Truncated and mutated constructs identified NF-kappaB and AP-1 binding sites as primary cis-acting elements in IL-8 gene transcription and IL-8 mRNA superinduction. Electrophoretic mobility shift assays indicated that CHI increased NF-kappaB and prolonged AP-1 DNA-binding activities and that the synergism of TNF-alpha and CHI on IL-8 mRNA expression was paralleled by a further increase of AP-1 DNA-binding activity. This synergism was still noticed when 4 h elapsed between the addition of CHI and that of TNF-alpha. Taken together, our results indicate that CHI interferes with both post-transcriptional and transcriptional repressive mechanisms of IL-8 mRNA expression.
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PMID:Enhanced AP-1 and NF-kappaB activities and stability of interleukin 8 (IL-8) transcripts are implicated in IL-8 mRNA superinduction in lung epithelial H292 cells. 946 40

Described is the identification of a novel series of compounds that blocks the activation of two key transcription factors, AP-1 and NF-kappa B. These transcription factors regulate the expression of several critical proinflammatory proteins and cytokines and represent attractive targets for drug discovery. Through the use of high throughput screening and solution-phase parallel synthesis, inhibitors of both NF-kappa B and AP-1 were identified. In subsequent testing, these compounds were also shown to block both IL-2 and IL-8 levels in the same cells. One of the most potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the importance of AP-1 and NF-kappa B as potential therapeutic targets. The synthesis and preliminary structure-activity relationships of these compounds is addressed.
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PMID:2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3',5'- bis(trifluoromethyl)phenyl)-carboxamide: a potent inhibitor of NF-kappa B- and AP-1-mediated gene expression identified using solution-phase combinatorial chemistry. 948 92

Elevated levels of circulating IL-8, a potent chemotactic factor for granulocytes and T lymphocytes, are found in HIV-infected individuals. The HIV-1 transactivator protein Tat increased IL-8 secretion in T cell lines following CD3- and CD28-mediated costimulation. Full-length Tat (Tat101) enhanced IL-8 transcription through up-regulated transcription factor binding to the CD28-responsive element (CD28RE) in the IL-8 promoter. Expression of the Tat splice variant Tat72 (72 amino acids) also enhanced IL-8 production following T cell stimulation via a different, most likely post-transcriptional, mechanism. The CD28RE in the IL-8 promoter was characterized as a low-affinity NF-kappaB binding site recognized by the transcription factors p50 (NF-kappaB1), p65 (RelA) and c-rel. Transcription factor binding to "classical" NF-kappaB sites in the HIV-1, the human IL-2, and lymphotoxin promoters, recognized by p50 and p65 following CD3+28-mediated costimulation, was unaffected by Tat101 as was binding to the AP-1 motif in the IL-8 promoter. These experiments identify the CD28RE in the IL-8 promoter as a c-rel recognition site and a Tat101-responsive element. The effect of Tat101 on CD28REs in the IL-8 promoter and the subsequent up-regulation of IL-8 secretion is likely to contribute to the immune dysregulation observed during HIV-1 infection.
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PMID:Superinduction of IL-8 in T cells by HIV-1 Tat protein is mediated through NF-kappaB factors. 951 Jan 90

Central to the pathogenesis of Salmonella typhimurium is its ability to engage the host cell in a two-way biochemical interaction. As a consequence of this interaction, a dedicated protein secretion system, termed type III, is activated in these bacteria and directs the translocation of signaling proteins into the host cell. Secretion of these proteins stimulates host cell signal transduction pathways that lead to a variety of cellular responses. An important feature of S. typhimurium pathogenesis is the induction of a profound inflammatory response in the intestinal epithelium. In this report, we show that S. typhimurium induces host cell signal transduction pathways that lead to the activation of the transcription factors NF-kappaB and AP-1, resulting in the production of proinflammatory cytokines such as IL-8. We also show that S. typhimurium infection of cultured intestinal epithelial cells results in the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38. Induction of these signaling pathways and the synthesis of IL-8 was strictly dependent on the function of the invasion-associated type III protein secretion system encoded by S. typhimurium. Pretreatment of cells with the highly specific p38 MAP kinase inhibitor SB 203580 prevented S. typhimurium-induced IL-8 production. These results indicate that the inflammatory response induced by S. typhimurium may be due to the specific stimulation of MAP kinase signaling pathways leading to nuclear responses.
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PMID:Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. 954 96

NF-kappaB plays a major role in the transcriptional regulation of many proinflammatory genes in multiple cell lineages, including intestinal epithelial cells (IEC). Activation of NF-kappaB requires both phosphorylation and degradation of its natural cytoplasmic inhibitor, IkappaB. We tested whether a super-repressor of NF-kappaB activity, which is a mutated nondegradable IkappaB alpha resistant to phosphorylation and degradation, could be delivered into IEC using an adenoviral vector (Ad5 IkappaB) and determined the antiinflammatory potential of this inhibitor following different stimuli. We showed for the first time that recombinant adenovirus efficiently infected (>80%) transformed as well as primary IEC. Cytoplasmic levels of the NF-kappaB super-repressor protein were more than 50-fold higher than those of endogenous IkappaB, and this mutated IkappaB was resistant to IL-1beta-induced degradation. Immunofluorescent RelA nuclear staining was strongly inhibited in Ad5 IkappaB-infected IEC compared with control Ad5LacZ and NF-kappaB, but not AP-1 binding activity, was reduced by more than 70% as measured by electrophoretic mobility shift assay (EMSA). Induction of inducible nitric-oxide synthase (iNOS), IL-1beta, and IL-8 genes by IL-1beta, TNF-alpha, or PMA was blocked in Ad5 IkappaB-infected cells but not in Ad5 LacZ controls as assayed by RT-PCR and ELISA. In addition, IL-1beta-induced IL-8 secretion was totally inhibited by Ad5 IkappaB in primary colonic IEC. We conclude that an adenoviral vector efficiently transfers a nondegradable IkappaB in both transformed and native IEC. The strong inhibition of NF-kappaB activity and the resulting down-regulation of multiple proinflammatory molecules by Ad5 IkappaB suggests an exciting approach for in vivo intestinal gene therapy and illustrates the key role of NF-kappaB in transcriptional regulation of the inflammatory phenotype of IEC.
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PMID:Inhibition of proinflammatory molecule production by adenovirus-mediated expression of a nuclear factor kappaB super-repressor in human intestinal epithelial cells. 955 98

The role of "oxidant-sensitive" transcription factors activator protein (AP)-1, nuclear factor (NF)-kappaB, and NF-IL6 in respiratory syncytial virus (RSV)-induced interleukin (IL)-8 gene expression in A549 epithelial cells was evaluated. RSV infection resulted in increased binding of each of these transcription factors. Transfection of A549 cells with plasmids containing serial truncations of the 5'-flanking region of the IL-8 gene revealed a positive cooperative effect of the binding sites for AP-1 and NF-kappaB. Mutation of either region markedly diminished responsiveness of the promoter to RSV. Mutation of the NF-IL6 site had minimal effect in the presence of intact binding sites for NF-kappaB and AP-1. The antioxidants NAC (N-acetylcysteine), DMSO, and DMPO (5,5-dimethyl-1-pyrroline N-oxide) did not inhibit RSV-induced binding of NF-kappaB; however, binding of AP-1 and NF-IL6 was inhibited. These observations suggest that AP-1 may be the preferred transcription factor (over NF-IL6) for cooperative interaction with NF-kappaB in RSV-induced IL-8 production.
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PMID:Activator protein-1 is the preferred transcription factor for cooperative interaction with nuclear factor-kappaB in respiratory syncytial virus-induced interleukin-8 gene expression in airway epithelium. 959 12

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