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)

The family of NF-kappaB/rel transcription factors regulates a variety of promoters through specific DNA-binding sites. Consistent with the role of NF-kappaB activation as a response to pathogens, it regulates the expression of immune modulating cytokines like interferon-beta3 (IFN-3). Transcriptional regulation of IFN-beta is characterized by strict constitutive repression and virus-mediated activation. A nuclear protein, called NRF (NF-kappaB repressing factor) silences constitutively the IFN-beta3 promoter by binding to the negative regulatory element (NRE). This control is achieved by a direct protein-protein interaction between NRF and proximal bound NF-kappaB factors preventing the transcriptional activation. After viral induction NRF still binds but does not any more exert its specific inhibition. NRE-related sequences found in a number of promoters like those of HIV-1, HTLV-1 and the genes of the IL-2Ralpha and IL-8 constitute functionally related silencer elements which repress the constitutive enhancing activity of NF-kappaB/rel-binding sites from these promoters.
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PMID:NRF, a nuclear inhibitor of NF-kappaB proteins silencing interferon-beta promoter. 1120 93

NF-kappaB plays a central role in mediating pathogen and cytokine-stimulated gene transcription. NF-kappaB repressing factor (NRF) has been shown to interact with specific negative regulatory DNA elements (NRE) to mediate transcriptional repression by inhibition of the NF-kappaB activity at certain promoters. mRNA ablation experiments demonstrated that the trans-acting NRF protein is involved in constitutive but not post-stimulated silencing of IFN-beta, IL-8 and iNOS genes by binding to cis-acting NRE elements in their promoters. We have examined the subcellular localization and mobility of the NRF protein. Since neither tagging nor overexpression perturbs NRF localization the GFP-tagged protein was used for detailed localization and mobility studies. Owing to an N-terminal nuclear localization sequence, all NRF fragments that contain this signal show a constitutive nuclear accumulation. C-terminal NRF fragments also localize to the nucleus although no canonical NLS motifs were detected. Full-length NRF is highly enriched in nucleoli and only a small fraction of NRF is found in the nucleoplasm and cytoplasm. This relationship was found to be independent of the protein expression rate. FRAP analysis proved to be a sensitive method to determine protein mobility and made it possible to differentiate between the NRF protein fragments. Nucleolar localization correlated inversely with mobility. The data demonstrate that a series of neighboring fragments in a large central domain of the protein contribute to the strong nucleolar affinity. These properties were not altered by viral infection or LPS treatment. Several sequence motifs for RNA binding were predicted by computer-mediated databank searches. We found that NRF binds to double stranded RNA (dsRNA). This property mapped to several NRF fragments which correlate with the nucleolar affinity domain. Since treatment with actinomycin D releases NRF from nucleoli the identified RNA binding motifs might act as nucleolar localization signals.
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PMID:Nucleolar localization and mobility analysis of the NF-kappaB repressing factor NRF. 1522 70

The trichothecene mycotoxin deoxynivalenol (DON), commonly present in contaminated grains worldwide, induces expression of the chemokine interleukin (IL)-8 in human monocytes. The purpose of this study was to test the hypothesis that DON modulates transcriptional and posttranscriptional regulation of IL-8 expression in the U937 human monocyte model. When U937 cells were transfected with a wild-type IL-8 promoter luciferase construct (-162/+44 IL-8 LUC) and incubated with DON (1 mug/ml) or the positive control, lipopolysaccharide (LPS) (1 mug/ml), there was a significant increase in luciferase expression. Mutation of the nuclear factor-kappaB (NF-kappaB) binding site significantly impaired both DON- and LPS-induced luciferase expression. In contrast, mutating the activator protein-1 binding site resulted in significantly increased DON- and LPS-induced luciferase expression. CCAAT/enhancer-binding protein beta, octamer-1, or NF-kappaB repressing factor binding site mutations did not affect DON-induced luciferase activity. Consistent with reporter studies, the NF-kappaB inhibitor caffeic acid phenethyl ester completely ablated both DON-induced IL-8 mRNA and protein expression. When NF-kappaB subunit binding to a specific IL-8 promoter probe was evaluated by enzyme-linked immunosorbent assay (ELISA), DON was observed to increase p65 binding by 21-fold, have no effect on p50 binding and decrease p52 binding. DON was not found to stabilize IL-8 mRNA in U937 cells. Taken together, these data suggest that DON-induced IL-8 expression is likely to be mediated at the transcriptional level by NF-kappaB, specifically p65, but does not appear to involve mRNA stabilization.
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PMID:Transcriptional regulation of deoxynivalenol-induced IL-8 expression in human monocytes. 1763 45

NF-kappaB repressing factor (NRF), a nuclear inhibitor of NF-kappaB, is constitutively expressed and is implicated in the basal silencing of specific NF-kappaB targeting genes, including IFN-beta, IL-8/CXCL8, and iNOS. Little is known about the regulation of NRF and its role in response to stimuli. Airway smooth muscle (ASM) is a rich source of inflammatory mediators that may regulate the development and progression of airway inflammation. We have previously reported that NE activates NF-kappaB in primary human ASM (hASM), leading to induction of TGF-beta1. In this study, we describe that, instead of inducing the NF-kappaB response gene IL-8/CXCL8, NE suppressed IL-8/CXCL8 release and mRNA expression in hASM cells. Transcriptional blockade studies using actinomycin D revealed a similar degradation rate of IL-8/CXCL8 mRNA in the presence or absence of NE, suggesting an involvement at the transcription level. Mechanistically, the NE repressive effect was mediated by inducing NRF, as shown by RT-PCR and Western blotting, which was subsequently recruited to the native IL-8/CXCL8 promoter leading to removal of RNA polymerase II from the promoter, as demonstrated by chromatin immunoprecipitation assays. Knockdown of NRF by small interfering RNA prevented NE-induced suppression of IL-8/CXCL8 expression. In contrast, NE did not induce NRF expression in A549 and Beas-2B cells, where NE only stimulates NF-kappaB activation and IL-8/CXCL8 induction. Forced expression of NRF in A549 cells by an NRF expression plasmid suppressed IL-8/CXCL8 expression. Hence, we describe a novel negative regulatory mechanism of NE-induced NRF, which is restricted to hASM and mediates the suppression of IL-8/CXCL8 expression.
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PMID:Neutrophil elastase represses IL-8/CXCL8 synthesis in human airway smooth muscle cells through induction of NF-kappa B repressing factor. 1954 52