Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the biological reactions to metal ions potentially released from prosthetic implants, we examined the ability of metal ions to produce bone-resorbing cytokines and the underlying mechanism using synoviocytes and bone marrow (BM) macrophages. The cells were incubated with NiCl(2), CoCl(2), CrCl(3) or Fe(2)(SO(4))(3) at optimal concentrations, which are detectable in joint fluid following total joint arthroplasty. The production of interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha were enhanced by all metal ions tested as determined by enzyme-linked immunosorbent assay. From the results of electrophoresis mobility shift assay, all metal ions enhanced the DNA-binding activity of nuclear factor kappaB (NF-kappaB), and p50-p65 heterodimers and p50 homodimers were the major subunits. These effects of the metal ions were considerably blocked by pyrrolidine dithiocarbamate (PDTC) known as a radical scavenger. An electron spin resonance study clearly demonstrated the ability of metal ions to generate activated oxygen species (AOS), especially hydroxyl radicals (*OH), which accounts for PDTC-blockade of metal ion-induced NF-kappaB activation and subsequent cytokine production. Taken together, our data raised the possibility that small amounts of metal ions released from prosthetic implants activate synoviocytes and BM macrophages through the AOS-mediated process (i.e. the redox pathway), and contribute to the initiation of osteolysis at the bone-implant interface.
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PMID:Metal ions induce bone-resorbing cytokine production through the redox pathway in synoviocytes and bone marrow macrophages. 1252 86

Although an aggressive phenotype of renal cell carcinoma (RCC) is known to frequently be associated with inflammatory paraneoplastic syndrome including serum C-reactive protein (CRP) elevation, the molecular mechanism underlying this clinical phenomenon as well as what yields the malignant phenotype leading to the progression of RCC has yet to be elucidated. Based on the increased level of inflammatory cytokines such as interleukin-6 in advanced cases of RCC, a cytokine-inducible transcription factor, namely, nuclear factor-kappa B (NF-kappa B), may thus play a role in the progression of RCC. An electrophoretic mobility shift assay (EMSA) was carried out to determine the activity of NF-kappa B. Out of 45 cases of RCC, 15 cases (33%) showed a >200% increase in the NF-kappa B activity in comparison with that seen in normal renal tissue. In locally advanced cases (> or =pT3), 64% (9/14) showed an increased activity whereas it was only observed in 19% (6/31) of localized cases (< or =pT2). All three cases with metastases showed an increased NF-kappa B activity. The NF-kappa B activity determined by EMSA was further confirmed by an immunohistochemical analysis using an antibody recognizing the nuclear localization signal (NLS) in p65 subunit of NF-kappa B. The serum CRP elevation correlated with the increased NF-kappa B activation, and therefore NF-kappa B may be a causative transcription factor of inflammatory paraneoplastic syndrome. A high NF-kappa B activity was associated with an increased expression of both the p65 and p50 subunits of NF-kappa B and a concomitant decreased expression of I kappa B alpha. No functional mutations of the I kappa B alpha gene were detected. The NF-kappa B activity may therefore be a late event in carcinogenesis related to tumor development, thereby representing a possible molecular target in the treatment of RCC.
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PMID:Increased nuclear factor-kappa B activation is related to the tumor development of renal cell carcinoma. 1266 95

Interleukin-6 (IL-6) secretion from endothelial cells (ECs) in response to mechanical stimuli plays an important role in the regenerative and inflammatory responses. The aim of this study was to determine the mechanism for the secretion of IL-6 from ECs in response to uni-axial continuous stretch. Continuous stretch induced IL-6 secretion from human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. Reverse transcriptase-polymerase chain reaction (RT-PCR) amplification showed that the transcription of the IL-6 gene peaked 2h after stretch. In vitro kinase assay of IkappaB kinase (IKKs) activity demonstrated that the activation of IKKs peaked 15 min after stretch. Two NF-kappaB inhibitors, pyrrolidine dithiocarbamanate (PDTC) and SN50, or antisense oligodeoxynucleotides for NF-kappaB p65 and p50 suppressed IL-6 mRNA expressions induced by continuous stretch. In conclusion, continuous stretch induces IL-6 secretion from ECs, most likely through sequential activation of IKKs and NF-kappaB.
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PMID:Stretch-induced IL-6 secretion from endothelial cells requires NF-kappaB activation. 1290 69

Alcoholic liver disease is associated with hepatic iron accumulation, and iron supplementation exacerbates alcoholic liver disease, suggesting the pathogenic role of iron in alcoholic liver disease. We have tested a hypothesis that iron plays a signaling role in activation of redox-sensitive nuclear factor-kappa B (NF-kappaB) and that increased iron content results in heightened expression of proinflammatory cytokines in Kupffer cells because of this signaling. In cultured Kupffer cells isolated from normal rats, treatment with a lipophilic iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), markedly reduced lipopolysaccharide (LPS)-induced NF-kappaB activation and expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6. Kupffer cells, isolated from rats with experimentally induced alcoholic liver disease, had significant increases in nonheme iron content, NF-kappaB binding, and mRNA expression for TNF-alpha and macrophage inflammatory protein-1. Ex vivo L1 treatment normalized all these parameters. Addition of ferrous iron to cultured normal rat Kupffer cells increased I-kappa B kinase (IKK) activity at 15 min and NF-kappaB binding at 30 min. L1 pretreatment completely abrogated both effects. Moreover, the iron treatment increased TNF-alpha release and TNF-alpha promoter activity in a NF-kappaB-dependent manner. Ferrous iron also transiently decreased cytoplasmic I-kappa B-alpha (IkappaB-alpha), with concomitant increases in nuclear p65 protein and DNA binding of p65/p50. Taken together, these results support the existence of iron-dependent signaling for activation of IKK/NF-kappaB in Kupffer cells, and this iron signaling serves as a target for a potential priming effect for the pathogenesis of experimental alcoholic liver disease.
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PMID:Iron-dependent activation of NF-kappaB in Kupffer cells: a priming mechanism for alcoholic liver disease. 1295 94

Adrenomedullin is a peptide found in a variety of cells and tissues and involved in a multitude of biological processes. Recently, adrenomedullin has been identified as a host defense peptide and as such it plays a role in the inflammatory response. The transcription factor NF-kappaB is a major regulator of genes involved in the inflammatory response and the aim of this study was to determine whether NF-kappaB played a role in the inflammatory process triggered by adrenomedullin. Skin epithelial cells (HaCaTs) were used as our model in vitro. Western blot analysis from adrenomedullin-stimulated HaCaT cells revealed a rapid degradation of NF-kappaB inhibitor alpha and beta followed by the translocation of free NF-kappaB to the nucleus, where it was detected by Texas Red immunostaining after incubation with adrenomedullin for 15 min. Electromobility shift assay showed that NF-kappaB present in the nucleus was active, since it bound to a probe containing an NF-kappaB binding site. Supershift assays indicated that p50 and p65, members of the NF-kappaB family, were both part of the NF-kappaB dimmers involved in adrenomedullin cell signaling. HaCaTs secreted interleukin-6 in response to AM, which was significantly attenuated by the NF-kappaB inhibitor SN-50. Taken together, the data lend support for an immunoregulatory role for AM.
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PMID:Adrenomedullin signals through NF-kappaB in epithelial cells. 1552 94

We report the program of gene expression during osteoclast formation from RAW264.7 cell precursors in response to RANK-ligand (RANK-L) using a combination of quantitative real time PCR and Affymetrix gene chip assays. We found that genes obligatory to osteoclast formation and function, namely tartrate-resistant acid phosphatase, cathepsin K, beta3 integrin, and calcitonin receptors, were up-regulated by RANK-L markedly by up to approximately 2000-fold. In contrast, we found a cluster of genes that were significantly down-regulated: these included interleukin-18, insulin-like growth factor-1, interleukin-6 receptor, and cathepsins B, C, and L. These results from real time PCR were broadly concordant with those obtained from Affymetrix. We also explored the expression of the transcription factors of the NFAT and NFkappaB family at days 3 and 5 of culture. Whereas NFATc1 expression was increased significantly at days 3 and 5 following RANK-L exposure, there were no significant increases in the expression of NFkappaB subunits, namely p65, p50, c-Rel, IkappaBalpha, and IkappaBbeta. There were also no significant differences in transcription modulator expression between days 3 and 5, except for c-Rel and NFATc4, which were both decreased significantly at day 5. The studies suggest RANK-L regulates the expression only of NFATc1, while it signals through both NFATc1 and NFkappaB.
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PMID:RANK-L induces the expression of NFATc1, but not of NFkappaB subunits during osteoclast formation. 1556 62

IkappaB-zeta is an inducible nuclear protein that interacts with nuclear factor-kappaB (NF-kappaB) via its carboxyl-terminal ankyrin-repeats. Previous studies using an NF-kappaB reporter have shown that IkappaB-zeta inhibits the activity of NF-kappaB. In the present study, we dissected the amino-terminal region of IkappaB-zeta, which shows no homology to any other proteins. Indirect immunofluorescence studies demonstrated the presence of a bipartite nuclear localization signal spanning amino acids 163-178. Using GAL4 fusion proteins, we found that internal fragments containing amino acids 329-402 possessed intrinsic transcriptional activation activity. Interestingly, the activity was not detected in GAL4 fusion proteins of the full-length IkappaB-zeta. On the other hand, the GAL4-dependent transcriptional activity was generated by co-expression of the GAL4-NF-kappaB p50 subunit fusion protein and the full-length IkappaB-zeta, neither of which exhibited the activity on their own. A new splicing variant, IkappaB-zeta(D), with a deletion of amino acids 236-429, was found to lack transactivation activity. Forced expression of IkappaB-zeta, but not IkappaB-zeta(D), augmented interleukin-6 production, indicating the functional significance of the transactivation activity. In contrast, tumor necrosis factor-alpha production was inhibited by expression of IkappaB-zeta, highlighting the dual functions of this molecule. These results indicate that IkappaB-zeta harbors latent transcriptional activation activity, and that the activity is expressed upon interaction with the NF-kappaB p50 subunit. In addition to the inhibitory activity on NF-kappaB-mediated transcription, the transcriptional activation activity of IkappaB-zeta should be crucial for the regulation of inflammation.
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PMID:Positive and negative regulation of nuclear factor-kappaB-mediated transcription by IkappaB-zeta, an inducible nuclear protein. 1561 16

In this study we addressed the role of the nuclear factor (NF)-kappaB1/p50 subunit in chronic injury of the liver by determining the inflammatory and fibrotic responses of nfkappab1-null mice in an experimental model that mimics chronic liver disease. Mice received repeated hepatic injuries throughout 12 weeks by intraperitoneal injection of the hepatotoxin carbon tetrachloride. In response nfkappab1(-/-) mice developed more severe neutrophilic inflammation and fibrosis compared to nfkappab1(+/+) mice. This phenotype was associated with elevated hepatic expression of tumor necrosis factor (TNF)-alpha, which was localized to regions of the liver associated with inflammation and fibrosis. Hepatic stellate cells are important regulators of hepatic inflammatory and fibrogenic events but normally do not express TNF-alpha. Hepatic stellate cells derived from nfkappab1(-/-) mice expressed TNF-alpha promoter activity, mRNA, and protein. By contrast the expression of other NF-kappaB-responsive genes (ICAM1 and interleukin-6) was similar between nfkappab1(-/-) and nfkappab1(+/+) cells. We provide experimental evidence that the inappropriate expression of TNF-alpha by nfkappab1(-/-) cells is because of lack of a p50-dependent histone deacetylase 1 (HDAC1)-mediated repression of TNF-alpha gene transcription. Taken together these data indicate that the p50 NF-kappaB subunit plays a critical protective role in the injured liver by limiting the expression of TNF-alpha and its recruitment of inflammatory cells.
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PMID:Nuclear factor-kappaB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. 1574 82

The estrogen receptor (ER) suppresses interleukin-6 (IL-6) gene expression through interaction with nuclear factor kappaB (NF-kappaB) in a hormone-dependent manner. Classic ER binding to DNA is not required and the mechanism of repression is unclear. Previously reported studies suggest that the interference of NF-kappaB binding to DNA by ER may play an important role. An alternative model for repression would be the disruption of NF-kappaB transactivation. In the present study, gel shift assays were used to examine the binding of RelA and p50 dimers to the IL-6 promoter in the presence of ER. The effect of ER on NF-kappaB transactivation was studied independent of NF-kappaB binding to DNA using the mammalian one-hybrid system. ER had little effect on the binding of homodimers or heterodimers of RelA and p50 to the IL-6 promoter. In transfection experiments, both ERalpha and ERbeta inhibited NF-kappaB-mediated expression in a hormone dependent manner with repression also dependent upon dimerization of RelA with p50. Mutant ER that is unable to transactivate failed to repress NF-kappaB expression, but deletion of the N-terminal portion of the receptor had no effect. Taken together, these results suggest that the disruption of NF-kappaB-mediated transactivation plays a significant role in ER inhibition of IL-6 gene expression.
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PMID:Estrogen receptor inhibits interleukin-6 gene expression by disruption of nuclear factor kappaB transactivation. 1604 58

Nuclear Factor-kappaB (NF-kappaB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular injury. We investigated the potential role of NF-kappaB activation in the pathogenesis of glomerular injury in 31 patients with class III-V lupus nephritis (LN), 14 patients with non-proliferative proteinuric glomerulopathy and six normal controls. The expression of NF-kappaB subunits p65 and p50, and the NF-kappaB regulated proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) as well as CD68 and synaptopodin was examined by Southwestern histochemistry (SWH) or immunohistochemistry. In contrast to non-proliferative glomerulopathy and normal controls, NF-kappaB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating cells in class IV LN, along with upregulation of TNF-alpha, IL-1beta, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial activation of NF-kappaB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage infiltration. Podocyte NF-kappaB overactivation (predominantly p65) paralleled podocyte expression of TNF-alpha and IL-1beta in patients with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-kappaB and p65 were positively correlated with the severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-kappaB in glomerular injury by multiple mechanisms.
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PMID:In situ glomerular expression of activated NF-kappaB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy. 1620 45


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