UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was aimed to investigate in elderly humans changes in NF-kappaB activation and in the expression of the inflammation-related genes inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) induced in peripheral blood mononuclear cells (PBMC) by acute eccentric exercise and by submaximal eccentric training. Eleven subjects, aged 66-75 years, carried out 2 bouts of eccentric exercise separated by 8 weeks of training. Following the first bout, NF-kappaB activation, and protein level of p50/p65 subunits, phospho-IkappaBalpha and phospho-IKKalpha increased, while IkappaBalpha protein level was significantly reduced. This was accompanied by a significant increase in iNOS, COX-2 and IL-6 mRNA protein level and protein content. Changes were significantly attenuated following the second exercise bout. In conclusion, acute eccentric exercise increases NF-kappaB activation and the expression of several inflammation-related genes in PBMC from elderly individuals. Regular eccentric training might be an effective method of preventing undesirable inflammatory responses induced by eccentric exercise.
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PMID:Eccentric training impairs NF-kappaB activation and over-expression of inflammation-related genes induced by acute eccentric exercise in the elderly. 1837 53

Although they share sequence homology to classical cytoplasmic I kappaB inhibitors of transcription factor NF-kappaB, the proteins I kappaB zeta, Bcl-3, and I kappa BNS function in the nucleus as factors that influence NF-kappaB-dependent gene expression profiles. Through the use of purified recombinant proteins and by comparison with the classical I kappaB protein I kappaB alpha, we have discovered mechanistic details of the interaction between I kappaB zeta and functional NF-kappaB dimers. Whereas I kappaB alpha and other classical I kappaB proteins bind tightly to NF-kappaB dimers that possess the p65 subunit, I kappaB zeta binds preferentially to NF-kappaB p50 homodimers. This altered specificity is particularly interesting in light of the fact that both NF-kappaB subunits exhibit high sequence and structural homology, while the I kappaB alpha and I kappaB zeta proteins are also conserved in primary amino acid sequence. We further show that I kappaB zeta is capable of forming a stable ternary complex with the NF-kappaB p50 homodimer and kappaB DNA. Again, this is a stark contrast from I kappaB alpha, which inhibits NF-kappaB p65 homodimer binding to NF-kappaB target DNA sequences. Removal of the DNA sequences flanking the NF-kappaB binding site does not directly affect the interaction of p50 and I kappaB zeta. Rather, we have discovered that the carboxy-terminal glycine-rich region of the NF-kappaB p50 homodimer is involved in mediating high-affinity binding of I kappaB zeta and NF-kappaB p50. We conclude that the NF-kappaB p50 homodimer functions as a legitimate activator of gene expression through formation of a ternary complex between itself, I kappaB zeta, and DNA. The requirement for formation of this complex could explain why the nuclear I kappaB protein I kappaB zeta is absolutely required for expression of the pluripotent pro-inflammatory cytokine interleukin-6 in peritoneal macrophages.
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PMID:The nuclear I kappaB protein I kappaB zeta specifically binds NF-kappaB p50 homodimers and forms a ternary complex on kappaB DNA. 1843 38

The major clinical challenge for cancer therapy remains the eradication or prevention of metastatic process. This study was an investigation of the antimetastatic activity of Biophytum sensitivum, using B16F-10 melanoma-induced experimental lung metastasis in C57BL/6 mice. B. sensitivum treatment significantly reduced lung tumor nodule formation accompanied by reduced lung collagen hydroxyproline, hexosamine, and uronic acid levels. Serum sialic acid and gamma-glutamyl transpeptidase levels were also significantly inhibited after B. sensitivum treatment. B. sensitivum treatment down-regulated the expression of matrix metalloprotease-2 and -9 and at the same time upregulated the lung tissue inhibitor of metalloprotease-1 and -2 expression. The cytokine profile and growth factors such as interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, granulocyte monocyte-colony stimulating factor, vascular endothelial growth factor, interleukin-2 and tissue inhibitor of metalloprotease-1 in the serum of these animals were markedly altered after B. sensitivum treatment. This altered level of cytokines after B. sensitivum treatment was also accompanied by enhanced natural killer cell and antibody-dependent cellular cytotoxicity. The study reveals that B. sensitivum treatment could alter proinflammatory cytokine production and could inhibit the activation and nuclear translocation of p65, p50, c-Rel subunits of nuclear factor-kappaB, and other transcription factors such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells.
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PMID:Anti-metastatic effect of Biophytum sensitivum is exerted through its cytokine and immunomodulatory activity and its regulatory effect on the activation and nuclear translocation of transcription factors in B16F-10 melanoma cells. 1847 42

The mechanism regulating radiation-induced anti-apoptotic response, a limiting factor in improving cell radiosensitivity, remains elusive. Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is the major member of MKPs that dephosphorylates and inactivates MAPK. Here we provide the evidence that MKP-1 was negatively bridging between NF-kappaB-mediated prosurvival pathway and c-Jun N-terminal kinase (JNK)-mediated proapoptotic response. MKP-1 was induced by gamma-radiation and repressed radiation-induced pro-apoptotic status. NF-kappaB RelA/p50 heterodimer was recruited to MKP-1 gene promoter to induce MKP-1 transcription. Deletion of the NF-kappaB-binding site or inactivation of NF-kappaB by its small interfering RNA significantly decreased the radiation-induced MKP-1 promoter activity. In addition, MKP-1-deficient mouse embryonic fibroblasts exhibited a prolonged activation of JNK but not p38 or extracellular signal-regulated kinase subfamilies of MAPKs. The prolonged activation of JNK was not induced by treatment with tumor necrosis factor alpha or interleukin-6, and inactivation of JNK but not p38 or ERK abolished radiation-induced proapoptotic status, indicating that JNK is specifically inhibited by radiation-induced MKP-1. Three MKP-1 wild type human tumor cell lines treated with MKP-1 small interfering RNA showed an increased proapoptotic response that can be rescued by overexpression of wild type mouse MKP-1. Together, these results suggest that MKP-1 is a NF-kappaB-mediated prosurvival effector in attenuating JNK-mediated pro-apoptotic response; NF-kappaB/MKP-1-mediated negative JNK regulation represents a potential therapeutic target for adjusting cell radiosensitivity.
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PMID:Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB regulation. 1850 59

Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. It has been shown to induce interleukin-6 (IL-6) expression in inflammatory responses in rheumatoid arthritis. We investigated the signaling pathway involved in IL-6 production caused by BK in synovial fibroblasts. BK caused concentration- and time-dependent increases in IL-6 production. By using pharmacological inhibitors or genetic inhibition of the BK receptor, siRNA revealed that B2 but not B1 BK receptors are involved in BK-mediated up-regulation of IL-6. BK-mediated IL-6 production was attenuated by phospholipase C inhibitor (U73122), protein kinase Cdelta inhibitor (rottlerin), NF-kappaB inhibitor (PDTC), IkappaB protease inhibitor (TPCK) and NF-kappaB inhibitor peptide. Stimulation of synovial fibroblasts with BK activated IkappaB kinase alpha/beta (IKK alpha/beta), IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus and kappaB-luciferase activity. BK mediated an increase of IKK alpha/beta and IkappaBalpha phosphorylation, kappaB-luciferase activity and p65 and p50 binding to the NF-kappaB element was inhibited by B2 BK receptor antagonist (HOE140), U73122 and rottlerin. Our results suggest that BK increased IL-6 production in synovial fibroblasts via the B2 BK receptor/PI-PLC/PKCdelta/and NF-kappaB signaling pathway.
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PMID:Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phospholipase C, protein kinase Cdelta and NF-kappaB pathway in human synovial fibroblasts. 1862 20

Nuclear factor kappa B (NF-kappaB) signaling is deregulated in many tumor types, resulting in aberrant expression and/or activation of NF-kappaB transcriptional complexes. We have previously reported that nuclear expression of the NF-kappaB subunit p50 is strongly correlated with melanoma progression and poor 5-year patient survival. In this study, we used cDNA microarray to analyze the gene expression profiles of melanoma cells overexpressing NF-kappaB p50. We found that NF-kappaB p50 expression strongly induced interleukin-6 (IL-6) upregulation in melanoma cells at both the transcriptional and translational levels and that IL-6 production by melanoma cells enhanced the growth of endothelial cells in vitro. Expression of activating transcription factor 3 (ATF3), a negative regulator of IL-6 gene transcription, inhibited p50-mediated IL-6 upregulation. Knockdown of p50 expression using lentiviral-based shRNA abrogated IL-6 induction in melanoma cells and inhibited its effects on endothelial cell growth. Finally, we used an in vivo matrigel plug assay to show that NF-kappaB p50 overexpression promotes angiogenesis, while silencing NF-kappaB p50 inhibits blood vessel formation. Our results demonstrate for the first time that the NF-kappaB p50 subunit mediates melanoma angiogenesis by specifically upregulating IL-6, highlighting a novel and important role for the NF-kappaB p50/IL-6 signaling axis in melanoma progression.
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PMID:Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin-6 expression. 1894 6

Anti-anaemic drug ferric-sorbitol citrate showed immunomodulatory effects, activating NF-kappaB in peritoneal macrophages, which consequently secrete tumour necrosis factor-alpha (TNF-alpha). TNF-alpha activates NF-kappaB in spleen cells. The aim of this study was to investigate the effect of iron polyisomaltosate, an iron (Fe(3+)) compound, on serum iron, interleukin-6 (IL-6) and serotonin (5-HT) concentration, neutrophil activity, and NF-kappaB activation in peritoneal macrophages and spleen cells in rats. Female Wistar rats were injected i.p. with 7.5mg iron/kg of iron polyisomaltosate 1.5, 3, 6, 24 and 48h before sacrifice. Serum iron, 5-HT and IL-6 concentration was determined by colorimetric, spectrofluorimetric and ELISA methods, neutrophil activity by a chemiluminescence assay, and NF-kappaB expression/activation by a Dot-Blot method. Iron polyisomaltosate significantly increased serum iron and 5-HT concentrations during the first 6h, IL-6 levels 3 and 6h, and diminished respiratory burst of granulocytes 1.5h after the injection. Iron polyisomaltosate stimulated activation of p65, p50 and RelB subunits of NF-kappaB in the peritoneal macrophages after 6h, and RelB subunit was additionally increased after 24 and 48h. In the spleen cells iron polyisomaltosate stimulated p65 subunit after 48h and RelB subunit after 24h. The results showed time-dependent immunomodulatory effects of iron polyisomaltosate. These effects might be achieved via induction of the intracellular signalling for NF-kappaB activation in peritoneal macrophages and later in spleen cells, together with increase of serum 5-HT, and IL-6 but with diminished respiratory burst of granulocytes. Iron polyisomaltosate presumably activated reactive oxygen species resulting in the stimulation of the acute phase reactants in the liver.
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PMID:Acute immunomodulatory effects of iron polyisomaltosate in rats. 1916 90

Primary effusion lymphoma (PEL) is a refractory malignancy caused by human herpes virus 8 (HHV-8) in immunocompromised individuals. The tumor cells of PEL are characterized by constitutive NF-kappaB activation. Dehydroxymethylepoxyquinomicin (DHMEQ) is a new NF-kappaB inhibitor and is effective on various tumor cells with constitutively activated NF-kappaB. Thus, in search for a new therapeutic modality of PEL, we examined the effect of DHMEQ on PEL cells. We confirmed constitutive activation of NF-kappaB with subcomponents of p50 and p65 in PEL cell lines. DHMEQ quickly and transiently abrogated NF-kappaB activation and reduced the cell viability in dose- and time-dependent manners, inducing apoptosis through activation of both mitochondrial and membrane pathways. Array analysis revealed that DHMEQ down-regulated expression levels of NF-kappaB target genes, such as interleukin-6 (IL6), Myc, chemokine (C-C motif) receptor 5 (CCR5) and NF-kappaB1, whereas it up-regulated expression levels of some genes involved in apoptosis, and cell cycle arrest. DHMEQ did not reactivate HHV-8 lytic genes, indicating that NF-kappaB inhibition by DHMEQ did not induce virus replication. DHEMQ rescued CB-17 SCID mice xenografted with PEL cells, reducing the gross appearance of effusion. Thus, DHMEQ transiently abrogated the NF-kappaB activation, irreversibly triggering the apoptosis cascade without HHV-8 reactivation. In addition, DHMEQ could rescue the PEL-xenograft mice. Therefore, we suggest DHMEQ as a promising candidate for molecular target therapy of the PEL.
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PMID:Transient inhibition of NF-kappaB by DHMEQ induces cell death of primary effusion lymphoma without HHV-8 reactivation. 1946 19

Inflammation is part of the host defense mechanism against harmful matters and injury; however, aberrant inflammation is associated to the development of chronic diseases such as cancer. Lunasin is a novel peptide that demonstrates potential anticancer activity against mammalian cancer cell lines and may play a role in inflammation. The objective of this study was to determine the mechanism of action by which lunasin and lunasin-like peptides exert their anti-inflammatory properties using RAW 264.7 macrophage cell line as an in vitro model. We purified three peptides (5, 8, and 14 kDa) from defatted soybean flour with a positive immunoreactivity towards lunasin mouse monoclonal antibody. Treatment with these peptides (10-50 microM) resulted in the inhibition of pro-inflammatory markers in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. The 5 kDa peptide inhibited most potently pro-inflammatory markers including interleukin-6 production (IC(50)=2 microM), interleukin-1beta production (IC(50)=13 microM), nuclear factor-kappa B (NF-kappaB) transactivation (IC(50)=21 microM), cyclooxygenase-2 expression (IC(50)=25 microM), nitric oxide production (IC(50)=28 microM), inducible nitric oxide synthase expression (IC(50)=37 microM), prostaglandin E(2) production (IC(50)=41 microM), p65 nuclear translocation (IC(50)=48 microM) and p50 nuclear translocation (IC(50)=77 microM). In conclusion, lunasin and lunasin-like peptides purified from defatted soybean flour inhibited inflammation in LPS-induced RAW 264.7 macrophage by suppressing NF-kappaB pathway.
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PMID:Lunasin and lunasin-like peptides inhibit inflammation through suppression of NF-kappaB pathway in the macrophage. 1968 18

To study the metabolic activity of NF-kappaB, we investigated phenotypes of two different mouse models with elevated NF-kappaB activities. The transcriptional activity of NF-kappaB is enhanced either by overexpression of NF-kappaB p65 (RelA) in aP2-p65 mice or inactivation of NF-kappaB p50 (NF-kappaB1) through gene knock-out. In these models, energy expenditure was elevated in day and night time without a change in locomotion. The mice were resistant to adulthood obesity and diet-induced obesity without reduction in food intake. The adipose tissue growth and adipogenesis were inhibited by the elevated NF-kappaB activity. Peroxisome proliferator-activator receptor gamma expression was reduced by NF-kappaB at the transcriptional level. The two models exhibited elevated inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) in adipose tissue and serum. However, insulin sensitivity was not reduced by the inflammation in the mice on a chow diet. On a high fat diet, the mice were protected from insulin resistance. The glucose infusion rate was increased more than 30% in the hyperinsulinemic-euglycemic clamp test. Our data suggest that the transcription factor NF-kappaB promotes energy expenditure and inhibits adipose tissue growth. The two effects lead to prevention of adulthood obesity and dietary obesity. The energy expenditure may lead to disassociation of inflammation with insulin resistance. The study indicates that inflammation may prevent insulin resistance by eliminating lipid accumulation.
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PMID:Uncoupling of inflammation and insulin resistance by NF-kappaB in transgenic mice through elevated energy expenditure. 2001 65

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