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)

We show that inhibitory effect of interleukin-13 on endotoxin-induced uveitis in the Lewis rat is dependent on signaling activity of protein kinase Czeta (PKCzeta). To understand the effect of interleukin-13 or PKCzeta inhibitor treatment, the activation status of rat bone marrow-derived macrophages was studied in vitro. At 6 hours, lipopolysaccharide-stimulated macrophages produced tumor necrosis factor-alpha (TNF-alpha) with nuclear factor kappaB (NF-kappaB)/p65 expression. Treatment led to absence of NF-kappaB/p65 expression and low levels of TNF-alpha, suggesting accelerated inactivation of macrophages. At 24 hours after lipopolysaccharide stimulation, nuclear NF-kappaB/p65 decreased and nuclear NF-kappaB/p50 increased, associated with nuclear BCL-3 and a low level of TNF-alpha, indicating onset of spontaneous resolution. Treatment limited PKCzeta cleavage, with expression of nuclear NF-kappaB/p50 and BCL-3 and low nuclear NF-kappaB/p65 promoting macrophage survival, as evidenced by Bcl-2 expression. At 24 hours, intraocular treatment decreased membranous expression of PKCzeta by ocular cells, reduced vascular leakage with low nitric-oxide synthase-2 expression in vascular endothelial cells, and limited inflammatory cell infiltration with decreased intraocular TNF-alpha, interleukin-6, and nitric-oxide synthase-2 mRNA. Importantly, treatment decreased nuclear NF-kappaB/p65, increased transforming growth factor-beta2, and reduced caspase 3 expression in infiltrating macrophages, implying a change of their phenotype within ocular microenvironment. Treatment accelerated endotoxin-induced uveitis resolution through premature apoptosis of neutrophils related to high expression of toll-like receptor 4 and caspase 3.
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PMID:Protein kinase Czeta (PKCzeta) regulates ocular inflammation and apoptosis in endotoxin-induced uveitis (EIU): signaling molecules involved in EIU resolution by PKCzeta inhibitor and interleukin-13. 1739 64

5-Androstenediol (5-AED) stimulates hematopoiesis and enhances survival in animals exposed to ionizing radiation (IR), suggesting that this steroid may act on hematopoietic progenitor cells. We used gamma-irradiated primary human CD34(+) hematopoietic progenitor cells to show that 5-AED protects hematopoietic cells from IR damage, as shown by enhanced cell survival, clonogenicity, proliferation, and differentiation. Unlike in tumor cells, IR did not induce nuclear factor-kappaB (NFkappaB) activation in primary progenitors. However, IR stimulated IkappaB(beta) release from NFkappaB/IkappaB complexes and caused NFkappaB1 (p50) degradation. 5-AED stabilized NFkappaB1 in irradiated cells and induced NFkappaB gene expression and NFkappaB activation (DNA binding). 5-AED stimulated interleukin-6 and granulocyte colony-stimulating factor (G-CSF) secretion. The survival-enhancing effects of 5-AED on clonogenic cells were abrogated by small interfering RNA inhibition of NFkappaB gene expression and by neutralization of G-CSF with antibody. The effects of 5-AED on survival and G-CSF secretion were blocked by the NFkappaB inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). 5-AED had no effect on accumulation of the proapoptotic factor p53 after IR, as determined by Western blot. The results indicate that NFkappaB1 degradation after IR may be responsible for the radiation sensitivity of CD34+ cells compared with tumor cells. 5-AED exerts survival-enhancing effects on irradiated human hematopoietic progenitor cells via induction, stabilization, and activation of NFkappaB, which results in increased secretion of hematopoietic growth factor G-CSF.
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PMID:5-Androstenediol promotes survival of gamma-irradiated human hematopoietic progenitors through induction of nuclear factor-kappaB activation and granulocyte colony-stimulating factor expression. 1747 57

This study was an investigation of the antimetastatic activity of amentoflavone using B16F-10 melanoma-induced experimental lung metastasis in C57BL/6 mice. Amentoflavone treatment significantly reduced tumor nodule formation accompanied by reduced lung collagen hydroxyproline, hexosamine, and uronic acid levels. Serum sialic acid and gammaglutamyl transpeptidase levels were also significantly inhibited after amentoflavone treatment. Amentoflavone treatment up-regulated the lung tissue inhibitor of metalloprotease-1 and tissue inhibitor of metalloprotease-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 amentoflavone treatment. This altered level of cytokines after amentoflavone treatment was also accompanied by enhanced natural killer cell antibody-dependent cellular cytotoxicity. The study reveals that amentoflavone 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:Effect of amentoflavone on the inhibition of pulmonary metastasis induced by B16F-10 melanoma cells in C57BL/6 mice. 1754 97

Coordinated expression and upregulation of interleukin-1alpha, interleukin-1beta, tumor necrosis factor-alpha, interleukin-6, granulocyte-macrophage colony-stimulating factor, interleukin-8, monocyte chemotactic protein-1 (MCP-1) and epithelial cell derived neutrophil activator-78, with chemoattractant and proinflammatory properties of various cytokine families, were obtained in the intestinal epithelial cell line Int407 upon Vibrio cholerae infection. These proinflammatory cytokines also showed increased expression in T84 cells, except for interleukin-6, whereas a striking dissimilarity in cytokine expression was observed in Caco-2 cells. Gene expression studies of MCP-1, granulocyte-macrophage colony-stimulating factor, interleukin-1alpha, interleukin-6 and the anti-inflammatory cytokine transforming growth factor-beta in Int407 cells with V. cholerae culture supernatant, cholera toxin, lipopolysaccharide and ctxA mutant demonstrated that, apart from cholera toxin and lipopolysaccharide, V. cholerae culture supernatant harbors strong inducer(s) of interleukin-6 and MCP-1 and moderate inducer(s) of interleukin-1alpha and granulocyte-macrophage colony-stimulating factor. Cholera toxin- or lipopolysaccharide-induced cytokine expression is facilitated by activation of nuclear factor-kappaB (p65 and p50) and cAMP response element-binding protein in Int407 cells. Studies with ctxA mutants of V. cholerae revealed that the mutant activates the p65 subunit of nuclear factor-kappaB and cAMP response element-binding protein, and as such the activation is mediated by cholera toxin-independent factors as well. We conclude that V. cholerae elicits a proinflammatory response in Int407 cells that is mediated by activation of nuclear factor-kappaB and cAMP response element-binding protein by cholera toxin, lipopolysaccharide and/or other secreted products of V. cholerae.
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PMID:Transcriptional upregulation of inflammatory cytokines in human intestinal epithelial cells following Vibrio cholerae infection. 1769 17

Binding of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) triggers expression of adhesive molecules and secretion of interleukin-6 (IL-6), promoting MM cell growth, survival, drug resistance, and migration, which highlights the possibility of developing and validating novel anti-MM therapeutic strategies targeting MM cells-host BMSC interactions and their sequelae. Recently, we have found that expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands can potently inhibit IL-6-regulated MM cell growth. Here we demonstrate that PPARgamma agonists 15-d-PGJ2 and troglitazone significantly suppress cell-cell adhesive events, including expression of adhesion molecules and IL-6 secretion from BMSCs triggered by adhesion of MM cells, as well as overcome drug resistance by a PPARgamma-dependent mechanism. The synthetic and natural PPARgamma agonists have diverging and overlapping mechanisms blocking transactivation of transcription factors NF-kappaB and 5'-CCAAT/enhancer-binding protein beta (C/EBPbeta). Both 15-d-PGJ2 and troglitazone blocked C/EBPbeta transcriptional activity by forming PPARgamma complexes with C/EBPbeta. 15-d-PGJ2 and troglitazone also blocked NF-kappaB activation by recruiting the coactivator PGC-1 from p65/p50 complexes. In addition, 15-d-PGJ2 had a non-PPARgamma-dependent effect by inactivation of phosphorylation of IKK and IkappaB. These studies provide the framework for PPARgamma-based pharmacological strategies targeting adhesive interactions of MM cells with the bone marrow microenvironment.
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PMID:Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARgamma cross talk with NF-kappaB and C/EBP. 1778 86

We previously reported that poncirin, a flavanone glycoside isolated from the EtOAc extract of the dried immature fruits of Poncirus trifoliata, is an anti-inflammatory compound that inhibits PGE(2) and IL-6 production. The present work was undertaken to investigate the molecular actions of poncirin in RAW 264.7 macrophage cell line. Poncirin reduced lipopolysaccharide (LPS)-induced protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the mRNA expressions of iNOS, COX-2, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in a concentration-dependent manner, as determined by Western blotting and RT-PCR, respectively. Furthermore, poncirin inhibited the LPS-induced DNA binding activity of nuclear factor-kappaB (NF-kappaB). Moreover, this effect was accompanied by a parallel reduction in IkappaB-alpha degradation and phosphorylation that in by nuclear translocations of p50 and p65 NF-kappaB subunits. Taken together, our data indicate that anti-inflammatory properties of poncirin might be the result from the inhibition iNOS, COX-2, TNF-alpha and IL-6 expression via the down-regulation of NF-kappaB binding activity.
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PMID:Inhibition of LPS-induced iNOS, COX-2 and cytokines expression by poncirin through the NF-kappaB inactivation in RAW 264.7 macrophage cells. 1805 24

In mammary gland infections, the contribution of NF-kappaB is not well defined, and was therefore investigated following intramammary inoculation of Escherichia coli. Non-invasive real-time in vivo imaging of the transcription factor activation was performed in mammary glands of transgenic mice expressing luciferase under the control of NF-kappaB. Bacterial inoculation resulted in a major increase in luminescence as compared with control glands. This activation was confirmed by immunohistochemical nuclear staining of the NF-kappaB p65 subunit in mammary epithelium of infected glands, while nuclear p50 was not detected. The systemic response to the intramammary inoculation of Escherichia coli was also studied. NF-kappaB activation in the liver increased over time, and a relatively mild but longer-lasting response was observed as compared with the acute hepatic response of mice receiving lipopolysaccharide. This systemic reaction was confirmed by increased circulating levels of the acute phase protein serum amyloid A, tumour necrosis factor-alpha and interleukin-6. In addition, high concentrations of both cytokines in the mammary gland inoculated with bacteria showed that the infection was also well established at the local level. These results indicate that in vivo monitoring of NF-kappaB activation is an attractive novel approach to study mammary gland inflammation, and that this transcription factor is imperative in the early stages of the host immune response towards coliform intramammary infections, both at the local and systemic level.
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PMID:In vivo imaging of NF-kappaB activity during Escherichia coli-induced mammary gland infection. 1824 Dec 10

In this study, the anti-inflammatory effects of flavonoids isolated from the roots of Glycyrrhiza uralensis (Leguminosae), namely, isoliquiritin (the glycoside of isoliquirigenin) and isoliquiritigenin (the aglycone of isoliquiritin) were evaluated on lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Isoliquiritigenin (ILG) more potently inhibited LPS-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production than isoliquiritin (ILT). Consistent with these findings, ILG reduced the LPS-induced expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein and mRNA levels in a concentration-dependent manner, as determined by Western blotting and RT-PCR, respectively. In addition, the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and the mRNA expression levels of these cytokines were reduced by ILG in a dose-dependent manner. Moreover, ILG attenuated the LPS-induced DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB), and this was associated with a decrease in inhibitory kappa B-alpha (IkappaB-alpha) phosphorylation and in the subsequent blocking of p65 and p50 protein translocations to the nucleus. Furthermore, ILG suppressed the phosphorylations of IkappaB kinase (IKK), ERK1/2, and p38, whereas the phosphorylation of JNK1/2 was unaffected. These results suggest that the anti-inflammatory properties of ILG are caused by iNOS, COX-2, TNF-alpha, and IL-6 down-regulation due to NF-kappaB inhibition via the suppression of IKK, ERK1/2 and p38 phosphorylation in RAW 264.7 cells.
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PMID:Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. 1829

In order to investigate whether weight loss can lead to improvement of the mononuclear cell (MNC) proinflammatory state, 21 nondiabetic obese women with mean age 34+/-2 years (mean+/-s.e.m.) and BMI 32.5+/-1.2 kg/m2 were enrolled in a 12-week caloric restriction and light exercise-based weight loss program. Ten lean women served as controls. Reverse transcription-PCR of proinflammatory cytokines and adipocytokines as well as homeostasis model assessment of insulin resistance (HOMA-IR) were determined before and after weight reduction. Nuclear factor kappaB (NF-kappaB) binding to DNA and inhibitors of NF-kappaB (IkappaB-alpha and IkappaB-beta) obtained from peripheral MNCs were measured. Overall, subjects lost a mean of 4.0+/-0.4 kg (5.0+/-0.3% of their initial body weight) (P<0.01). In addition to significant reductions in BMI, fasting glucose and insulin concentrations, mean serum high-sensitivity C-reactive protein (hs-CRP), migration inhibitor factor (MIF), leptin and visfatin levels decreased by 49.0, 66.6, 17.2, and 50.2%, respectively (all P<0.05), while adiponectin concentrations rose by 33.9% (P<0.05). The DNA binding of the transcriptionally active NF-kappaB from (p65/p50) decreased by 38.1% (P<0.05). Elevated levels of mRNA of NF-kappaB related proinflammatory genes, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), MIF, and matrix metalloproteinase-9 (MMP-9), decreased significantly after weight loss. Although mRNA expression of Rel-A, p105, IkappaB-alpha, IkappaB-beta decreased significantly, their protein levels did not change after weight loss. As a group, NF-kappaB binding activity correlated with HOMA-IR (r=0.332, P=0.049) and marginally with values of BMI (r=0.308, P=0.059). In conclusion, weight loss by 5% of initial weight in nondiabetic obese women led to significant improvement in activated intranuclear NF-kappaB binding as well as several transcriptions of proinflammatory genes regulated by NF-kappaB.
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PMID:Effect of weight loss on proinflammatory state of mononuclear cells in obese women. 1939 76

In response to bacterial challenges, fibroblasts, a major constituent of gingival connective tissue, can produce immunoregulatory cytokines and proteolytic enzymes that may contribute to tissue destruction and the progression of periodontitis, a chronic inflammatory disease affecting tooth-supporting tissues, including alveolar bone. The spirochete Treponema denticola is a major etiological agent of periodontitis and can invade oral tissues. The aim of the present study was to investigate the inflammatory response of gingival fibroblasts to T. denticola lipooligosaccharide (LOS). T. denticola LOS induced significant production of various inflammatory mediators by fibroblasts, including interleukin-6, interleukin-8, monocyte chemoattractant protein 1, nitric oxide, and prostaglandin E(2). In addition, the secretion of matrix metalloproteinase 3, an enzyme active on basement membrane components, was also significantly increased. The response of fibroblasts was dose-dependent and much stronger following a 24 h stimulation period. The expression and/or phosphorylation state of several signaling proteins, including Fos, MKK1, MKK2, MKK3/6, NF-kappaB p50, and NF-kappaB p65, was enhanced following stimulation of fibroblasts with T. denticola LOS. In summary, T. denticola LOS induced an inflammatory response in gingival fibroblasts and may thus contribute to the immunopathogenesis of periodontitis and the progression of the disease.
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PMID:Treponema denticola lipooligosaccharide activates gingival fibroblasts and upregulates inflammatory mediator production. 1836 71


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