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)

Interleukin-8 (IL-8), a chemotactic cytokine for T lymphocytes and neutrophils, is induced in several cell types by a variety of stimuli including the inflammatory cytokines IL-1 and tumor necrosis factor alpha TNF-alpha. Several cis elements, including a binding site for the inducible transcription factor NF-kappa B, have been identified in the regulatory region of the IL-8 gene. We have examined the ability of various NF-kappa B subunits to bind to, and activate transcription from, the IL-8 promoter. A nuclear complex was induced in phorbol myristate acetate-treated Jurkat T cells which bound specifically to the kappa B site of the IL-8 promoter and was inhibited by addition of purified I kappa B alpha to the reaction mixture. Only antibody to RelA (p65), but not to NFKB1 (p50), NFKB2 (p50B), c-Rel, or RelB was able to abolish binding, suggesting that RelA is a major component in these kappa B binding complexes. Gel mobility shift analysis with in vitro-translated and purified proteins indicated that whereas the kappa B element in the human immunodeficiency virus type 1 long terminal repeat bound to all members of the kappa B/Rel family examined, the IL-8 kappa B site bound only to RelA and to c-Rel and NFKB2 homodimers, but not to NFKB1 homodimers or heterodimers of NFKB1-RelA. Transient transfection analysis demonstrated a kappa B-dependent expression of the IL-8 promoter in a human fibrosarcoma cell line (8387) and in Jurkat T lymphocytes. Cotransfection with various NF-kappa B subunits indicated that RelA and c-Rel, but neither NFKB1 nor heterodimeric NFKB1-RelA, was able to activate transcription from the IL-8 promoter. Furthermore, cotransfection of NFKB1 and RelA, although able to support activation from the human immunodeficiency virus type 1 long terminal repeat, failed to activate expression from the IL-8 promoter. Antisense oligonucleotides to RelA, but not NFKB1, inhibited phorbol myristate acetate-induced IL-8 production in Jurkat T lymphocytes. These data demonstrate the differential ability of members of the kappa B/Rel family to bind to, and activate transcription from, the IL-8 promoter. Furthermore, while providing a novel example of a kappa B-regulated promoter in which the classical NF-kappa B complex is unable to activate transcription from the kappa B element, these data provide direct evidence for the role of RelA in regulation of IL-8 gene expression.
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PMID:NF-kappa B subunit-specific regulation of the interleukin-8 promoter. 841 15

Interleukin 1beta (IL-1beta) up-regulates human rheumatoid synovial fibroblast (RSF) 85-kDa phospholipase A2 (PLA2) and mitogen-inducible cyclooxygenase (COX) II. Promoter regions for these genes contain a motif that closely resembles the "classic" NFkappaB consensus site. Immunoblot analysis identified NFkappaB1 (p50), RelA (p65), and c-Rel in RSF. Upon IL-1beta-stimulation, p65 and c-Rel but not p50 protein levels were reduced suggesting nuclear translocation. IL-1beta-induced RSF nuclear extracts contained a p65-containing complex, which bound to the classical NFkappaB consensus motif. An NFkappaB classical oligonucleotide decoy produced a concentration-dependent decrease in IL-1-stimulated PGE2 production (IC50 = approximately 2 microM), indicating a role of NFkappaB. Utilization of antisense technology showed that p65 but not p50 or c-Rel mediated IL-1beta-stimulated PGE2 formation. Treated RSF could not transcribe COX II or 85-kDa PLA2 mRNA, which reduced their respective proteins. Interestingly, stimulated IL-8 production was not inhibited by the classical NFkappaB decoy but was reduced by treatment with antisense to both p65 and c-Rel supporting preferential binding of c-Rel-p65 to the "alternative" IL-8 kappaB motif. Taken together, these data provide the first direct evidence for a role of p65 in COX II and 85-kDa PLA2 gene induction and support the IL-1 activation and participation of distinct NFkappaB protein dimers in RSF prostanoid and IL-8 formation.
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PMID:Manipulation of distinct NFkappaB proteins alters interleukin-1beta-induced human rheumatoid synovial fibroblast prostaglandin E2 formation. 894 Jan 64

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

Pulmonary epithelial cells, covering a 70-m2 surface area, have not previously been considered an important source of chemokines in pulmonary tuberculosis. We analyzed IL-8 secretion from A549 cells and primary normal human bronchial epithelial cells (NHBE) infected by Mycobacterium tuberculosis. Direct infection of A549 cells by M. tuberculosis caused IL-8 secretion of 7720 +/- 1610 pg/106 cells, but no IL-8 secretion from NHBE after 24 h. In contrast, conditioned media from M. tuberculosis-infected human monocytes (CoMTB) induced a much greater IL-8 secretion of 92,635 +/- 13,180 pg/106 A549 cells and 13,416 +/- 3,529 pg/106 NHBE after 24 h. CoMTB induced rapid IL-8 mRNA accumulation, which was stable over 24 h, compared with TNF-alpha-induced transcripts. CoMTB stimulated nuclear binding of p65, p50, and c-Rel subunits of NF-kappa B to IL-8 promoter sequences. Transient transfections with IL-8 promoter reporter constructs showed NF-kappa B binding-site mutations abolished IL-8 promoter activity while NF-IL-6 binding-site mutations decreased promoter activity to 50.2 +/- 6.3% of wild-type activity. IL-1R antagonist but not neutralizing anti-TNF-alpha inhibited epithelial cell IL-8 secretion, mRNA accumulation, and NF-kappa B binding. Recombinant IL-1 beta (2 ng/ml) induced similar levels of IL-8 secretion to CoMTB in both A549 cells and NHBE. Pulmonary epithelial cells are a major source of IL-8 in the initial host response to pulmonary tuberculosis. Such IL-8 secretion is NF-kappa B dependent, NF-IL-6 requiring, and activated by an IL-1-mediated pathway as a consequence of phagocytosis of M. tuberculosis by monocytes.
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PMID:Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network. 1049 Sep 95

Activation of T cells through the antigen-specific T-cell receptor in combination with a costimulatory signal results in efficient cytokine gene transcription. The CD28-induced signal represents a major costimulatory signal for T cells. A CD28 response element, named CD28RE, was first identified in the interleukin-2 (IL-2) promoter region. Here we demonstrate that the NF-kappaB sequence in the IL-6 promoter functions as a CD28 response element. Mutations in this sequence rendered the IL-6 promoter unresponsive to CD28 costimulation. Moreover, this element could replace the IL-2 CD28RE in conferring CD28 responsiveness to the IL-2 promoter. In analogy to the known CD28 response elements IL-2 CD28RE, IL-8 CD28RE, and the human immunodeficiency virus-1 (HIV-1) NF-kappaB motif, the IL-6 NF-kappaB motif efficiently bound c-Rel, c-Rel/NFKB1, and the recently identified inducible T-cell factor NF-MATp35. However, the IL-6 NF-kappaB sequence together with the IL-8 CD28RE and HIV-1 NF-kappaB sequence differed from the IL-2 CD28RE in the binding of NF-kappaB/Rel family proteins. Although the IL-2 CD28RE exerted selective binding with c-Rel and c-Rel/NFKB1, the other CD28REs allowed efficient binding of a wide range of NF-kappaB/Rel family proteins. The difference in binding specificity correlated with the capacity of the distinct CD28 response elements to function in the context of the IL-6 promoter in response to T-cell activation. Domain swapping experiments revealed that the IL-8 CD28RE and HIV-1 NF-kappaB motif conferred similar responsiveness as the genuine IL-6 NF-kappaB motif in the transcriptional activation of the IL-6 promoter upon CD28 costimulation. In contrast, replacement of the IL-6 NF-kappaB sequence by the IL-2 CD28RE motif strongly reduced the responsiveness of the IL-6 promoter. These data indicate that despite the sequence similarity, two different classes of CD28 responsive elements exist that differ in their NF-kappaB binding capacity and the ability to confer CD28 costimulatory responsiveness toward a heterologous promoter.
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PMID:Functional disparity of distinct CD28 response elements toward mitogenic responses. 1056 14

Infection of human epithelial cells with human rhinovirus (HRV)-16 induces rapid production of several proinflammatory cytokines, including IL-8, IL-6, and GM-CSF. We evaluated the role of NF-kappaB in HRV-16-induced IL-8 and IL-6 production by EMSA using oligonucleotides corresponding to the binding sites for NF-kappaB in the IL-6 and IL-8 gene promoters. Consistent with the rapid induction of mRNA for IL-8 and IL-6, maximal NF-kappaB binding to both oligonucleotides was detected at 30 min after infection. NF-kappaB complexes contained p65 and p50, but not c-Rel. The IL-8 oligonucleotide bound recombinant p50 with only about one-tenth the efficiency of the IL-6 oligonucleotide, even though epithelial cells produced more IL-8 protein than IL-6. Neither the potent glucocorticoid, budesonide (10-7 M), nor a NO donor inhibited NF-kappaB binding to either cytokine promoter or induction of mRNA for either IL-8 or IL-6. Sulfasalazine and calpain inhibitor I, inhibitors of NF-kappaB activation, blocked HRV-16-induced formation of NF-kappaB complexes with oligonucleotides from both cytokines, but did not inhibit mRNA induction for either cytokine. By contrast, sulfasalazine clearly inhibited HRV-16 induction of mRNA for GM-CSF in the same cells. Thus, HRV-16 induces epithelial expression of IL-8 and IL-6 by an NF-kappaB-independent pathway, whereas induction of GM-CSF is at least partially dependent upon NF-kappaB activation.
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PMID:Role of NF-kappa B in cytokine production induced from human airway epithelial cells by rhinovirus infection. 1097 57

NF-kappaB/Rel transcription factors have been implicated in the differentiation of monocytes to either dendritic cells (DCs) or macrophages, as well as in the maturation of DCs from antigen-processing to antigen-presenting cells. Recent studies of the expression pattern of Rel proteins and their inhibitors (IkappaBs) suggest that their regulation during this differentiation process is transcriptional. To investigate differential gene expression between macrophages and DCs, we used commercially available gene microarrays (GEArray KIT), which included four of the NF-kappaB/Rel family genes (p50/p105, p52/p100, RelB, and c-rel) and 32 additional genes either in the NF-kappaB signal transduction pathway or under transcriptional control of NF-kappaB/Rel factors. To generate macrophages and DCs, human adherent peripheral blood monocytes were cultured with M-CSF or GM-CSF + IL-4 respectively for up to 8 days. DCs (and in some experiments, macrophages) were treated with lipopolysaccharide (LPS) for the last 48 h of culture to induce maturation. Cells were harvested after 7 days, cDNA was prepared and radiolabeled with alpha-(32)P-dCTP, then hybridized to gene arrays containing specific gene probes. beta-actin and GAPDH or PUC18 oligonucleotides served as positive or negative controls, respectively. The expression of all four NF-kappaB/Rel family genes examined was significantly upregulated in maturing DCs compared to macrophages. The strongest difference was observed for c-rel. RT-PCR determinations of c-rel, RelB, and p105 mRNAs confirmed these observations. Among the 32 NF-kappaB/Rel pathway genes, 14 were upregulated in mature DCs compared to macrophages. These genes were IkappaBalpha, IKK-beta, NIK, ICAM-1, P-selectin, E-selectin, TNF-alpha, TNFR2, TNFAIP3, IL-1alpha, IL-1R1, IL-1R2, IRAK, and TANK. By contrast, only mcp-1 (monocyte chemotactic protein 1) was upregulated in macrophages compared to DCs. NF-kappaB pathway genes upregulated in DCs compared to macrophages were constitutively expressed in monocytes then selectively downregulated during macrophage but not DC differentiation. LPS did not induce expression of most of these genes in macrophages but LPS did induce upregulation of IL-8 in mature macrophages. We conclude that NF-kappaB/Rel family genes, especially c-rel, are selectively expressed during differentiation of monocytes towards DCs. Moreover, this differential expression is associated both with activation of different NF-kappaB signal transduction pathways in DCs and macrophages and with expression of a unique subset of genes in DCs that are transcriptionally targeted by NF-kappaB/Rel factors. The results illustrate the ability of the NF-kappaB pathway to respond to differentiation stimuli by activating in a cell-specific manner unique signalling pathways and subsets of NF-kappaB target genes.
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PMID:Expression of different NF-kappaB pathway genes in dendritic cells (DCs) or macrophages assessed by gene expression profiling. 1157 45

The effects of WR1065 (SH), the free thiol form of amifostine, on nuclear transcription factor kappaB (NFkappaB) activation, manganese superoxide dismutase (MnSOD) gene expression, and secretion of human vascular endothelial cell growth factor (hVEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin, and interleukins IL-1alpha, IL-6, and IL-8 were investigated and compared in human microvascular endothelial (HMEC) and human glioma cells. WR1065 was evaluated at 2 concentrations, 4 mmol/L, ie, its most effective cytoprotective dose, and 40 micromol/L, a noncytoprotective but highly effective dose capable of preventing radiation and chemotherapeutic drug-induced mutations in exposed cells. A 30-minute exposure of HMEC and glioma cell lines U87 and U251 to WR1065 at either of the concentrations resulted in a marked activation of NFkappaB as determined by a gel shift assay, with the maximum effect observed between 30 minutes and 1 hour after treatment. Using a supershift assay, WR1065 exposure was observed to affect only the p50-p65 heterodimer, and not the homodimers or heterodimers containing p52 or c-Rel subunits of NFkappaB. WR1065 was also found to enhance MnSOD gene expression in both HMEC and glioma cells. Gene expression was enhanced 1.8-fold over control levels in HMEC over a period ranging from 12 to 24 hours after the time of maximum activation of NFkappaB. In contrast, MnSOD gene expression in U87 cells rose 3.5 times above control levels over this same period. WR1065 had no effect on the levels of adhesion molecules, cytokines, and growth factors secreted by cells exposed for up to 24 hours as measured by enzyme-linked immunosorbent assay.
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PMID:Differential activation of nuclear transcription factor kappaB, gene expression, and proteins by amifostine's free thiol in human microvascular endothelial and glioma cells. 1191 94

Alprazolam is a hypnotic/tranquilizer that has been shown to specifically inhibit the platelet-activating factor (PAF)-induced aggregation of human platelets. The goal of this study was to elucidate whether alprazolam modulates IL-1alpha-initiated responses. For this purpose we investigated the effects of alprazolam on the IL-1alpha-induced production of inflammatory cytokines (IL-8 and monocyte chemoattractant protein 1 (MCP-1)) in a human glioblastoma cell line, T98G, and explored the signaling pathways involved. We found that alprazolam inhibited IL-1alpha-elicited MCP-1 production within a range of 0.1-3 micro M. In contrast, it did not inhibit IL-1alpha-induced IL-8 production. Although NF-kappaB is involved in regulating the IL-1alpha-induced expression of MCP-1 and IL-8, the degradation of IkappaB-alpha stimulated by IL-1alpha was not inhibited by alprazolam. Alprazolam prevented NF-kappaB from binding to the MCP-1 promoter region (the A2 and A1 oligonucleotide probes), but binding of NF-kappaB to IL-8/NF-kappaB was not inhibited. Moreover, alprazolam inhibited c-Rel/p50 binding to the A2 oligonucleotide probe, but not p50/p65 from binding to the IL-8/NF-kappaB site. While AP-1 is involved in regulating the IL-1alpha-induced expression of IL-8, but not MCP-1, alprazolam potentiated the binding of c-Jun/c-Fos to the AP-1 oligonucleotide probe. These results show that the inhibition of IL-1alpha-mediated MCP-1 production by alprazolam is mainly due to inhibition of c-Rel/p65 and c-Rel/p50 binding to the MCP-1 promoter region, since alprazolam did not affect the IL-1alpha-mediated activation of NF-kappaB (p50/p65) or AP-1 (c-Jun/c-Fos) binding to the IL-8 promoter region. In conclusion, a new action of alprazolam was elucidated, as shown in the inhibition of c-Rel/p65- and c-Rel/p50-regulated transcription.
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PMID:Suppression of monocyte chemoattractant protein 1, but not IL-8, by alprazolam: effect of alprazolam on c-Rel/p65 and c-Rel/p50 binding to the monocyte chemoattractant protein 1 promoter region. 1221 54

The generation of cytokines, particularly TNF-alpha, by mast cells is crucial for the initiation of the allergic response. A key transcription factor involved in the synthesis of TNF-alpha is NF-kappaB. Using a mAb specific for the activated form of NF-kappaB, immunocytochemistry, confocal microscopy, and gel shift assays have been used in conjunction to localize this transcription factor to human lung mast cells and to study its activation. Activation of mast cells with stem cell factor (10 ng/ml) and anti-IgE (1 micro g/ml) induced maximal activation of NF-kappaB at 4 and 2 h, respectively. In contrast, with TNF-alpha (5 ng/ml) maximal activation occurred within 15 min. Parallel falls in IkappaB were demonstrated. Confocal microscopy demonstrated the localization of the activated form of NF-kappaB to the nuclei of activated mast cells. NF-kappaB activation was verified using a gel shift assay. A supershift assay showed mast cell NF-kappaB to be composed primarily of p50 with smaller amounts of p65. No interaction with Abs for Rel-A, c-Rel, Rel-B, and p52 was seen. Immunocytochemistry and ELISAs showed TNF-alpha to be stored within mast cells and released into the extracellular environment following activation. The possible participation of TNF-alpha generated by mast cells in NF-kappaB activation by anti-IgE was investigated using a blocking Ab for TNF-alpha. The blocking Ab reduced NF-kappaB activation by anti-IgE by >50%, suggesting that the release of preformed mast cell-associated TNF-alpha acts as a positive autocrine feedback signal to augment NF-kappaB activation and production of further cytokine, including GM-CSF and IL-8.
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PMID:NF-kappa B and TNF-alpha: a positive autocrine loop in human lung mast cells? 1239 Dec 48

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