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)

Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease, helps to protect the epithelial surface of the airways from the destructive capacity of neutrophil elastase. Based on the recognition that SLPI levels can increase in the presence of airway inflammation, we hypothesized that inflammatory stimuli should modulate the expression of the SLPI gene in airway epithelial cells. To evaluate this, the modulation of SLPI gene expression with various inflammatory stimuli was evaluated in the HS-24 human bronchial epithelial cell line. After preliminary studies showed that several inflammatory mediators enhanced SLPI messenger RNA (mRNA) levels, PMA was used as a model inflammatory stimulus. PMA significantly increased the level of 0.7-kb SLPI mRNA transcripts in HS-24 cells in a dose- and time-dependent fashion and increased the amount of SLPI protein in the culture supernatant. Nuclear run-on analyses showed that the SLPI gene transcription rate increased approximately twofold after PMA stimulation. Transfection studies using fusion genes composed of fragments of up to 1.2 kb of the 5' flanking sequence of the SLPI gene and a luciferase reporter gene demonstrated potent promoter activity in the 131-bp segment (-115 to +16 relative to the transcription start site), and all longer segments up to 1.2 kb, whereas smaller segments showed low promoter activity. An 18-bp element (-98 to -115), in a region with homology to PMA-responsive regions in the Moloney murine leukemia virus enhancer and the IL-8 gene, was shown to be of importance in the level of transcription of the SLPI gene. However, this element was not responsible for the upregulation of SLPI gene expression by PMA. Evaluation of HS-24 cells in the presence of actinomycin D demonstrated that SLPI mRNA transcripts were very stable and became more so in the presence of PMA. Thus, SLPI gene expression in airway epithelial cells can be upregulated by an inflammatory stimulus, and this modulation is regulated at both the transcriptional and posttranscriptional levels. These mechanisms of SLPI upregulation likely play a role in defending the epithelial surface in the local milieu of inflammatory lung diseases.
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PMID:Modulation of secretory leukoprotease inhibitor gene expression in human bronchial epithelial cells by phorbol ester. 791 12

Fibroblasts play an indirect augmenting effector role in the inflammatory response by releasing growth and differentiation factors and other inflammatory mediators after activation by inflammatory cytokines such as interleukin (IL)-1, but whether direct activation occurs by exogenous agents such as endotoxin (lipopolysaccharide, LPS) remains controversial. Using a number of primary human airways tissue-derived fibroblast lines, we demonstrate that in contrast to IL-1 alpha, LPS significantly induced gene expression and production of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-8, and IL-6 only in nasal but not bronchial or lung tissue-derived fibroblasts. Enhanced expression was dose- and time-dependent, and the minimal stimulatory dose was 10 ng LPS/ml. Polymyxin B entirely abrogated increased cytokine expression by LPS. Actinomycin D treatment largely inhibited expression, and LPS markedly increased an IL-6 gene promoter-driven luciferase reporter response in transfected nasal fibroblasts, suggesting enhanced expression may involve transcriptional regulation. Secondary protein or IL-1 synthesis requirement seemed unlikely since cycloheximide superinduced LPS-stimulated cytokine expression and anti-IL-1 alpha/beta antibodies failed to abrogate the response. Thus our data show that GM-CSF, IL-8, and IL-6 are directly inducible in nasal fibroblasts by LPS, and establish heterogeneous responsiveness to LPS by different fibroblast populations in the airways.
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PMID:Lipopolysaccharide induces expression of granulocyte/macrophage colony-stimulating factor, interleukin-8, and interleukin-6 in human nasal, but not lung, fibroblasts: evidence for heterogeneity within the respiratory tract. 839 62

We examined the biological function of a nonstructural regulatory protein, NS1, of human parvovirus B19. Because of the cytotoxic activity of NS1, human hematopoietic cell lines, K562, Raji, and THP-1, were established as transfectants which produce the viral NS1 protein upon induction by using bacterial lactose repressor/operator system. NS1 was significantly produced in the three transfectant cells in an inducer dose- and time-dependent manner. Surprisingly, these three transfectants secreted an inflammatory cytokine, interleukin-6 (IL-6), in response to induction. However, no production of other related cytokines, IL-1beta, IL-8, or tumor necrosis factor alpha, was seen. Moreover, NS1-primed IL-6 induction was transiently demonstrated in primary human endothelial cells. Analysis with luciferase reporter plasmids carrying IL-6 promoter mutant fragments demonstrated that NS1 effect is mediated by a NF-kappaB binding site in the IL-6 promoter region, strongly implying that NS1 functions as a trans-acting transcriptional activator on the IL-6 promoter. Our novel finding, IL-6 induction by NS1, supports the possible relationship between parvovirus B19 infection and polyclonal activation of B cells in rheumatoid arthritis and indicates that NS1 protein may play a significant role in the pathogenesis of some B19-associated diseases by modulating the expression of host cellular genes.
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PMID:A cytotoxic nonstructural protein, NS1, of human parvovirus B19 induces activation of interleukin-6 gene expression. 897 Sep 71

The nuclear factor kappaB (NF-kappaB) regulates the transcription of genes bearing the kappaB consensus motif. Transmigration of NF-kappaB from the cytoplasm to the nucleus is regulated by the IkappaB family of inhibitory NF-kappaB-binding proteins. Dissociation of the NF-kappaB-IkappaB complex requires both phosphorylation and degradation of IkappaBs. We demonstrate that IL-1beta induces complete IkappaB alpha degradation in Caco-2 cell lines but not in HT-29, T84, SW-480 transformed cell lines, or native colonic epithelial cells. A similar lack of IkappaB alpha degradation in HT-29 cells followed TNF-alpha and bacterial polymer stimulation. IL-1beta stimulated NF-kappaB nuclear translocation and NF-kappaB-dependent IL-1beta and IL-8 expression in both Caco-2 and HT-29 cells as assayed by electrophoretic mobility shift assay, immunofluorescence, kappaB-luciferase transfection, reverse transcriptase-PCR analysis and ELISA. In HT-29 cells stimulated with IL-1beta, IkappaB alpha was phosphorylated and when cycloheximide blocked new protein synthesis, IkappaB alpha was partially degraded. NF-kappaB cytoplasmic to nuclear transmigration was incomplete and preceded IkappaB alpha degradation in 9T-29 cells, in contrast to complete coordinated NF-kappaB nuclear translocation and IkappaB alpha degradation in Caco-2 cells. Greater sensitivity of HT-29 cells to a calpain inhibitor, as measured by IL-8 secretion, suggested enhanced resistance to IkappaB alpha proteolysis. These data show that IL-1beta induces NF-kappaB activity and expression of NF-kappaB-dependent genes in colonic epithelial cells and suggest altered regulation of IkappaB alpha degradation compared with other cell lineages, which may result in their increased responsiveness to therapeutic blockade.
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PMID:Evidence for altered regulation of I kappa B alpha degradation in human colonic epithelial cells. 897 94

Infection of the lung epithelial cell line A549 by respiratory syncytial virus (RSV) resulted in the elevated synthesis of multiple cellular cytokines, including a number of interleukins (ILs). Detailed studies of IL-11 induction revealed that it required infection by viable virus and involved a net increase in the steady state level of IL-11 mRNA. Nuclear run-on assays showed a direct effect of RSV on IL-11 gene transcription. Mutational analysis of the IL-11 promoter fused to a reporter luciferase gene demonstrated the requirement of a region 720 nucleotides upstream of the mRNA start site in the transcriptional induction of IL-11 by RSV. Two nearly identical 10-nucleotide-long sequences GGGGTCTCCC and GGGTCTCCCC in this region resembled the NF-kappa B consensus motif. Mutation of either sequence greatly reduced RSV-mediated induction of IL-11 promoter activity. NF-kappa B sites in IL-1 alpha, IL-6, and IL-8 promoters were also required for RSV-mediated induction of transcription of these promoters. Immunological studies and use of reporter gene constructs provided direct evidence for the activation and nuclear translocation of NF-kappa B by RSV. Sodium salicylate and aspirin, inhibitors of NF-kappa B activation, abolished transcriptional induction of all these cytokines by RSV. Together, these studies demonstrated an essential role of NF-kappa B in RSV-mediated transcription of multiple cytokines genes and suggested a possible use of salicylates in managing airway inflammation and viral pathogenesis during RSV infection.
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PMID:Transcriptional induction of multiple cytokines by human respiratory syncytial virus requires activation of NF-kappa B and is inhibited by sodium salicylate and aspirin. 919 51

Transcriptional activation of the expression of the gene for interleukin (IL)-8) in airway epithelial cells was analyzed by stable transfection of human bronchial epithelial cells (16 HBE) with a reporter plasmid pIL-8/Luc, which the expression of luciferase reporter gene is driven by human IL-8 promoter. As compared with the resting condition, the luciferase activity was 3.9 times higher after stimulation with phorbol-myristate-acetate (20 ng/ml), 1.6 times higher after stimulation with tumor necrosis factor-alpha (100 U/ml), and 2.7 times higher after stimulation with interleukin-1 beta (100 U/ml). Dexamethasone inhibited the effects of these stimulants by 10 to 50 percent. These results closely correspond to those of IL-8 mRNA analyses with Northern blotting and IL-8 protein analyses done by enzyme-linked immunosorbent assay. The transgenic cell line IL-8 Luc/16HBE can also be used in screening for drug effects, and may be useful for quantifying IL-8 inducibility in clinical samples obtained from the lungs.
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PMID:[Analysis of IL-8 gene transcription in human bronchial epithelial cells by stable transfection of a reporter gene]. 929 92

Neutrophil infiltration is a well-documented early event in the pathogenesis of rhinovirus (RV) infections. To further understand the mechanisms responsible for this neutrophilia, we determined whether interleukin (IL)-8 was present at sites of experimental RV infection in vivo and characterized the mechanism(s) by which RV stimulates IL-8 production in vitro. IL-8 was readily detectable in the nasal washings of all normal volunteers and did not increase with sham nasal inoculation. In contrast, RV infection caused a significant additional increase in nasal IL-8, the levels of which peaked 48-72 h after virus inoculation. RV was a potent stimulator of IL-8 protein production by A549 epithelial-like cells, MRC-5 fibroblasts, and normal human bronchial epithelial cells in vitro. This induction was associated with a significant increase in IL-8 mRNA accumulation and gene transcription. RV also stimulated IL-8 promoter-driven luciferase activity. This stimulation was significantly decreased by mutation of the nuclear factor (NF)-IL-6 site and was completely abrogated by mutation of the NF-kappaB site in this promoter. In addition, NF-kappaB-DNA binding activity was rapidly induced in RV-infected cells. This inducible binding was made up of p65 and, to a lesser extent, p50 NF-kappaB moieties. These studies demonstrate that IL-8 is present in normal nasal secretions and that the levels of IL-8 are further increased after RV infection. They also demonstrate that RVs are potent stimulators of IL-8 production and that this induction is mediated, at least in part, by an NF-kappaB-dependent transcriptional activation pathway. IL-8 may contribute to the pathogenesis of RV infection, and NF-kappaB activation may be a central event in RV-induced pathologies.
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PMID:Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB. 935 57

Thrombin is the central bioregulatory enzyme in hemostasis and is generated in vascular beds in which inflammatory responses are ongoing. In this study, we examined the effect of thrombin, both alone and in combination with TNF, on gene expression in porcine aortic endothelial cells (EC). Thrombin (1-10 U/ml) induced increased mRNA levels of E-selectin, monocyte chemoattractant protein-1, IL-8, plasminogen activator inhibitor-1, and IkappaB-alpha. These effects were mimicked by a thrombin receptor-activating peptide; preincubation of thrombin with hirudin blocked the induction of mRNA, suggesting that the increased gene expression was due to thrombin-specific activity. Because these genes are known to contain nuclear-factor-kappaB (NF-kappaB)-binding elements in their promoter region, we next examined the ability of thrombin to activate this transcription factor. As detected by electrophoretic mobility shift assay, thrombin (10 U/ml) or thrombin receptor-activating peptide (100 microM) stimulated increased NF-kappaB-binding activity. Supershift analysis revealed that these complexes were comprised principally of the RelA (p65) and NF-kappaB1 (p50) Rel family members. Thrombin alone did not substantively increase protein levels of E-selectin despite the increase in E-selectin mRNA levels. However, thrombin (3-10 U/ml) stimulated a 10-fold enhancement in the ability of TNF (0.3-1.0 ng/ml) to induce E-selectin surface expression. Similar potentiation of TNF-induced NF-kappaB activity and E-selectin transcription by thrombin was observed in experiments utilizing luciferase reporter constructs expressed in bovine aortic EC. The ability of thrombin to potentiate TNF-induced EC activation thus provides an important mechanism by which products of the coagulation cascade may enhance cytokine-mediated inflammatory responses.
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PMID:Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF. 954 5

In 16HBE transformed human bronchial epithelial cells, histamine stimulated interleukin (IL)-8 mRNA and protein secretion, and this histamine stimulation was inhibited by the H1-receptor antagonist diphenhydramine (DPH), by the inhibitor of 5-lipoxygenase-activating protein (FLAP) MK-886, by the 5-lipoxygenase inhibitor Zileuton, and by dexamethasone. Histamine stimulated bronchial epithelial cell production of leukotriene B4 (LTB4), and this production was inhibited by FLAP inhibitors MK-886 and L-655,238 and Zileuton. Histamine stimulated IL-8 luciferase reporter gene activity that was inhibited with DPH, dexamethasone, MK-886 and L-655,238, and Zileuton. The inhibition of IL-8 transcription and protein secretion by FLAP inhibitors and Zileuton was reversed with exogenous LTB4. There was increased IL-8 nuclear factor-kappaB (NF-kappaB) DNA-binding activity after histamine stimulation, and this was inhibited by DPH and MK-886. Cytoplasmic phospholipase A2 mRNA levels were also potently induced by histamine. Thus histamine stimulation of bronchial epithelial cells involves binding at H1 receptors, production of LTB4, activation of NF-kappaB and increased expression of IL-8.
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PMID:Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells. 960 43

Fine particles in the air have been associated with increased mortality and morbidity. Particulate air pollution is a complex mixture which varies by region and includes a number of components including residual oil fly ash (ROFA), a byproduct of power plant and industry fuel-oil combustion. Human airway epithelial cells exposed to ROFA release inflammatory cytokines including interleukin (IL)-6, IL-8, and tumor necrosis factor. Expression of these genes is dependent upon pretranscriptional binding of cis regulatory elements, including nuclear factor kappaB (NF-kappaB). To investigate the role of NF-kappaB in the particulate-induced IL-6 response, we exposed human airway epithelial cells (BEAS-2B) to ROFA in vitro. ROFA stimulated a time- and dose-dependent increase in IL-6 messenger RNA (mRNA), which was preceded by the activation of nuclear proteins binding to the NF-kappaB sequence motif in the IL-6 promoter. Transient transfection of BEAS-2B cells with the 5' promoter region of the IL-6 gene linked to a luciferase reporter gene confirmed that NF-kappaB binding is necessary for the transcription of IL-6 mRNA. The IL-6 response was inhibited by the metal chelator deferoxamine and the free radical scavenger N-acetyl-L-cysteine, suggesting that the activation of NF-kappaB may be mediated through reactive oxygen intermediates generated by transition metals found in ROFA. Activation of NF-kappaB may therefore be a critical first step in the inflammatory cascade following exposure to particles generated by oil combustion.
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PMID:Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB activation. 965 Nov 85

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