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

The effects of interleukin-6 (IL-6) on interferon regulatory factor 1 (IRF-1) gene expression were studied in B-hybridoma B9 cells which are growth-stimulated by IL-6 and breast carcinoma T47D cells which are growth-inhibited. IL-6 induced the production of IRF-1 mRNA and protein in both cell types, but IRF-1 binding activity to its target DNA sequence was induced only in T47D cells. With B9 cells, there was no IRF-1 binding but instead strong constitutive binding of the IRF-2 repressor, indicating that binding of IRF-1 to DNA is an important regulatory step. The IRF-1 gene promoter element, palindromic IFN-response element (pIRE), was found to respond to IL-6 with high efficiency as compared with IFN-gamma or IFN-beta. On this palindromic TTC...GAA sequence, two protein complexes (pIRE-a and pIRE-b) were induced within minutes by IL-6. pIRE-b is similar to the main complex induced by IFN-gamma and contains the Stat91 protein. pIRE-a predominantly induced by IL-6 is a slowly migrating complex which does not contain Stat91 and has low affinity for IFN-gamma activated sequence (GAS)-type sequences. Comparison of the relative effects of IL-6 and IFN-gamma shows that pIRE enhancers are differently regulated than GAS elements. Distinct transcription complexes, forming in ratios dependent on the inducer, help explain how various cytokines sharing effects through Stat91 on related enhancers can produce specific patterns of gene expression. Activation of the pIRE-a factors defines a novel transcriptional activity of IL-6 in epithelial and lymphoid cells.
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PMID:Induction by interleukin-6 of interferon regulatory factor 1 (IRF-1) gene expression through the palindromic interferon response element pIRE and cell type-dependent control of IRF-1 binding to DNA. 816 91

Previous studies have revealed that human breast fibroblasts secrete the cytokine, interleukin-6 (IL-6) which stimulates the ability of MCF-7 human breast carcinoma cells to convert estrone (E1) to the biologically more active 17 beta-estradiol (E2). This is mediated by an increase in reductive 17 beta-hydroxysteroid dehydrogenase (17-HSD) activity. In the studies described here, we have extended our observations using the anti-estrogen, tamoxifen, to demonstrate that in a steady state, endogenous intracellular concentrations of E2 have no effects on reductive 17-HSD activity (E1-->E2), but are already maximally inhibitory for the oxidative reaction (E2-->E1). Increasing intracellular concentrations of E2, however, stimulated the reductive 17-HSD in a dose-dependent manner. IL-6 stimulated the reductive pathway and was synergistic with E2. IL-6 is most likely acting through an E2-dependent mechanism, since tamoxifen completely reversed the effects of E2 and IL-6 separately and in combination. These observations suggest that tamoxifen may reduce intratissular levels of E2 by directly increasing oxidative 17-HSD activity and by blocking the actions of paracrine factors such as IL-6 which increase reductive 17-HSD activity.
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PMID:The anti-estrogen tamoxifen blocks the stimulatory effects of interleukin-6 on 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. 824 Sep 83

The study was initiated as an in vitro approach to the situation existing during intravesical bacillus Calmette-Guerin (BCG) instillation in patients with superficial bladder cancer. Cytokine secretion of a human bladder carcinoma cell line T24 treated with BCG was investigated. A 24-h treatment of T24 cells with BCG resulted in a tenfold higher secretion of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) when compared with T24 cells treated with Escherichia coli, Streptococcus faecalis or a cell wall preparation of Nocardia rubra (N-CWS). No secretion of IL-1 beta and IL-2 was detected. Pre-exposing T24 cells to BCG for various periods of time indicated that a minimum exposure time of 0.5-1 h was required to upregulate IL-6 and TNF alpha production. Extending the BCG pre-exposure time to 2 and 3 h further increased the rate of cytokine production. No significant difference was found, however, between the rate of secretion initiated after a 2-h or 3-h pre-exposure period. The amounts of these cytokines secreted in the presence of BCG-conditioned medium did not differ significantly from the constitutively secreted amounts, excluding an effect of products possibly secreted by BCG on the upregulation of IL-6 and TNF alpha. In addition, upregulation of cytokine production appeared to be dependent on the concentration of BCG. The results suggest that cytokines may be produced by urothelial tumor cells after intravesical instillation in patients with superficial bladder cancer, which may play a role in the mode of action of BCG.
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PMID:Cytokine production by the human bladder carcinoma cell line T24 in the presence of bacillus Calmette-Guerin (BCG). 827 92

Many factors have been implicated in the etiology of cervical neoplasia, with human papilloma virus being the latest in a long line of agents that may on their own or in combination exert various initiating and promoting effects on cervical cells, resulting in their transformation. However, for such altered cells to become invasive, it is clear that they must undergo alterations in their rate of turnover, state of differentiation, and motility. We have investigated the production of the multifunctional cytokine interleukin-6 (IL-6) by five new cervical carcinoma cell lines (XH1, EH2, DE3, JE6, and SM7) and the commercially available CaSki cell line, and have studied the effects of this cytokine on the growth of the cells in vitro. All the cell lines produce biologically active IL-6 in amounts varying between 0.35 to 2.0 ng/ml. In the presence of goat anti-sera to IL-6 all the tumor cell lines showed inhibition of growth. IL-6 acts as an autocrine growth factor for in vitro cervical tumor cell growth.
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PMID:Interleukin-6 (IL-6) functions as an autocrine growth factor in cervical carcinomas in vitro. 834 58

The present study was undertaken to investigate whether modulation of interleukin-6 and interleukin-1 production occurs owing to keratinocyte-fibroblast interaction. Normal human keratinocytes or squamous carcinoma cells were cultured either alone or in the presence of human foreskin fibroblasts or murine 3T3 cells. All cells tested produced interleukin-6, and interleukin-6 levels were markedly increased when normal or malignant keratinocytes were co-cultured with fibroblasts. The bioassay (species independent) and enzyme-linked immunosorbent assay (specific for human interleukin-6) together with use of complementary DNA probes specific for human or murine interleukin-6 revealed that fibroblasts are responsible for increased interleukin-6 levels. Moreover, interleukin-6 levels were increased when fibroblasts were cultured in conditioned media derived from normal human keratinocytes and squamous carcinoma cells-4 cultures. Interleukin-1 alpha secreted by normal human keratinocytes and squamous carcinoma cells-4 cells was mainly responsible for the increased interleukin-6 production in fibroblasts. Although interleukin-1 activity increased linearly with the incubation time in squamous carcinoma cells-4 monocultures, interleukin-1 activity was low and remained unchanged in squamous carcinoma cells-4/3T3 co-cultures. Low interleukin-1 activity was most probably not due to inhibition of interleukin-1 alpha production in squamous carcinoma cells-4/3T3 co-cultures because interleukin-1 alpha messenger RNA expression in squamous carcinoma cells-4 cells remained unchanged in the presence of 3T3 cells. Furthermore, when 3T3 cells were incubated in conditioned medium derived from squamous carcinoma cells-4 cells, high interleukin-1 activity decreased to an undetectable level, suggesting that fibroblasts are involved in the suppression of interleukin-1 activity. The remaining interleukin-1 activity, however, was sufficient for maximal induction of interleukin-6 production in fibroblasts. These results suggest that the interaction between epithelial and mesenchymal cells is at least partly initiated by interleukin-1 alpha secreted by the activated epithelial cell during skin injury or tumor invasion. Interleukin-1 in turn can induce modulation of the synthesis of various pro-inflammatory mediators and proteases in surrounding fibroblasts. An enhanced proteolytic activity and/or a possible induced production of an interleukin-1 inhibitor in fibroblasts and/or a receptor-mediated interleukin-1 consumption by fibroblasts will cause a decrease in interleukin-1 activity and thus exert a negative feedback.
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PMID:Modulation of IL-6 production and IL-1 activity by keratinocyte-fibroblast interaction. 837 Sep 68

Tumour necrosis factor-alpha (TNF) induced a cytotoxic response in ME-180 human cervical carcinoma cells in vitro. This cytotoxic response was accompanied by a temporal series of intracellular signals that are commonly triggered by a mitogenic stimulus: increased c-fos (20-30 min) and c-myc (40-60 min) expression, increased activity of ornithine decarboxylase (3 h), increased intracellular polyamine content (7 h) and increased thymidine incorporation into DNA (14 h). A cytotoxic response independent of these mitogenic signals could not be explained by an induction of interleukin-6, which is an autocrine cytotoxic agent in some cell types; nor by a biphasic, dose-dependent response in which low concentrations of TNF are mitogenic and higher concentrations are cytotoxic. Conversely, a dependent role of these mitogenic signals was suggested by the absence of a TNF-promoted increase in thymidine incorporation into DNA in an ME-180 clone that is resistant to TNF-induced cytotoxicity. A decrease in the proliferation rate of TNF-sensitive cells induced by either alpha-difluoromethylornithine treatment (resulting in polyamine depletion) or serum starvation rendered the cells insensitive to TNF-induced cytotoxicity, further suggesting a role for mitogenic signals and cell division in TNF-mediated cytotoxicity. However, inhibiting proliferation with cycloheximide resulted in increased sensitivity to TNF, implying that mitogenesis itself was not essential for a cytotoxic response. TNF induced DNA fragmentation in sensitive cells, suggesting that cytotoxicity occurred via apoptosis.
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PMID:Tumour necrosis factor-induced cytotoxicity is accompanied by intracellular mitogenic signals in ME-180 human cervical carcinoma cells. 843 87

We investigated the anti-tumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic Lewis lung-carcinoma clone, D122. These cells express high-affinity IL-6 receptors at numbers comparable to the IL-6-dependent murine hybridoma B9 cells; however, IL-6 did not affect D122 cell proliferation or expression of MHC-class-I antigens in vitro. In vivo, treatment of mice bearing D122 tumors in the footpads, with a low dose of IL-6 in 3 daily injections, 4 days a week for 3 weeks, significantly decreased spontaneous metastases. However, only combined treatment of IL-6 and irradiated tumor cells resulted in almost complete protection against spontaneous metastases. Histological analysis confirmed the absence of micrometastases in most of the animals treated by this combination protocol. Analysis of the cytolytic activity of splenocytes at various time points during combined IL-6 and immunotherapy of tumor-bearing mice revealed significant and sustained lysis of the poorly immunogenic D122 carcinoma cells, while splenocytes of control mice could not lyse D122 target cells. Activation of specific immunity was also demonstrated when mice were pre-immunized with hrIL-6 and inactivated D122 cells and challenged with live carcinoma cells 10 days later. Significant growth inhibition of the primary tumor was observed.
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PMID:Combined therapy with IL-6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas. 844 6

Oligonucleotide primers for human interleukin-6 (IL-6) that bracketed the entire coding region of the gene were used in reverse transciptase-polymerase chain reaction (RT-PCR) studies to examine lL-6 expression in peripheral blood mononuclear cells (PBMC). In addition to the predicted 0.64-kb RT-PCR product, a second 0.45-kb product was observed. Cloning and dideoxy sequence analysis of this product revealed evidence for an alternatively spliced lL-6 transcript lacking exon II. Further RT-PCR analysis using forward primers ending at or one base before the exon I donor splice site again yielded both products. Additional primers were designed and successfully used to selectively distinguish the two forms of IL-6 transcript. Both transcripts were prominent in peripheral blood monocytes and lymphocytes, whereas only the 0.64-kb, full-length transcript was prominent in the lL-6-producing 5637 (human bladder carcinoma) cell line. Northern analysis revealed, in addition to the predominant 1.3-kb transcript, several minor transcripts at 1.9 to 4.8 kb that hybridized with the alternatively spliced cDNA probe but not with an exon II probe. Western analysis revealed lL-6 polypeptides of predicted size (26 to 29 kD) in culture medium from PBMC, while showing an immunoreactive band at 17 kD in cell lysates. These findings suggest the existence of an alternatively spliced form of lL-6 mRNA, which would encode for a polypeptide missing the gp130 interactive (signal-transducing) domain contained in exon II while retaining the lL-6 receptor (p80) domain. Such a molecule could in theory function as a natural antagonist of lL-6, as it would be expected to bind to the IL-6 receptor but not lead to signal transduction.
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PMID:Detection and analysis of an alternatively spliced isoform of interleukin-6 mRNA in peripheral blood mononuclear cells. 854 46

Nude mice bearing the human oral cavity carcinoma cell line OCC-1, and the lung cancer cell line LC-1, developed a triple paraneoplastic syndrome consisting of hypercalcemia, cachexia and leukocytosis. All of these abnormalities disappeared rapidly after surgical resection of the tumors, suggesting their ectopic humoral nature. Search for the factors responsible for the respective abnormalities revealed that the production of parathyroid hormone-related protein and colony-stimulating factors (CSFs), mainly granulocyte-CSF, by the tumors could explain the hypercalcemia and leukocytosis, respectively. With regard to the severe cachexia, the production of two cachexia-associated cytokines, interleukin-6 and leukemia inhibitory factor, was able to explain the syndrome in OCC-1 bearing nude mice; however, the factor responsible in LC-1 bearing nude mice could not be identified. The triple paraneoplastic syndrome that developed in these two animal models could be explained partly by concomitant production of the peptide hormone and cytokines by cancer cells. These animal models may be very useful for the evaluation of diagnostic and therapeutic modalities for humoral abnormalities.
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PMID:Triple paraneoplastic syndrome of hypercalcemia, leukocytosis and cachexia in two human tumor xenografts in nude mice. 860

In order to assess the impact of surgical trauma involved in the therapy of esophageal carcinoma on the cellular immune system, a perspective study was performed involving perioperative hematological parameters. The activity of natural killer cells and the serum concentrations of interleukin-2, interleukin-6 and TNF-alpha were measured in 12 cases of transmediastinal dissection and 10 cases of transthoracic en bloc esophageal resection and compared to values of a control group of thoracic and abdominal surgical patients with non-malignant maladies. Natural killer cells assume a central role in the non-specific immunological response in tumor patients. Their main function is the destruction of tumor cells via cytotoxic activities amplified by the release of interleukin-2 and TNF-alpha. Natural killer cell activity was measured prior to surgery and on postoperative days 4 and 10 using a standardized europium chloride release assay, utilizing K562 target cells. Lymphokines interleukin-2, interleukin-6, and TNF-alpha were also measured on postoperative days 1 and 7 using standardized ELISA assays. The activity of natural killer cells in our patient group sank significantly (P < 0.05) on postoperative day 4 and likewise in the control group and both study groups, activity sank to the original values. In the control group, natural killer cell activity averaged 45% of preoperative values, in comparison with an average of 63% following transmediastinal esophageal carcinoma resection (one cavity procedure), and transthoracic en bloc resection (two cavity procedure). On postoperative day 10, all groups displayed a significant reacceleration of natural killer cell activity (P < 0.05). Whereas transthoracic en bloc resection patients only reached 61% of preoperative values, transmediastinal dissection patients assumed 75%, and 77% was achieved by control group members. Transthoracic en bloc resection of the esophagus led to a more extreme reduction in cytotoxic cellular activity owing to the greater surgical trauma. Suppression of the immunological tumor resistance, especially in the vulnerable perisurgical phase, can have an indirect negative effect on the manifestation risk of hematogenic metastases owing to intraoperative tumor cell dissemination resulting from tumor manipulation and may thus be prognostically relevant.
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PMID:[Effect of surgical trauma on NK cell activity in esophageal carcinoma after transmediastinal dissection vs. transthoracic en bloc resection]. 876 78


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