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)

A comparative study of the molecular mechanism of interleukin-6 (IL-6) gene induction on two breast-carcinoma-derived cell lines has been performed. MDA-MB-231 cells produce constitutive detectable levels of both secreted IL-6 and mRNA which, as expected, are dramatically enhanced following induction by either IL-1 beta or tumor necrosis factor-alpha (TNF-alpha). The levels of both secreted IL-6 and IL-6 mRNA are significantly higher in response to IL-1 beta in spite of the fact that stimulation by TNF-alpha alone enhances the half life of IL-6 mRNA. The protein synthesis inhibitor cycloheximide is also a fairly strong inducer of IL-6 in these cells. In contrast, MCF-7 cells fail to produce detectable IL-6 protein or mRNA, even after stimulation with proper inducers. Analysis of transcription factors NF-kappa B, NFIL6 and NFIL6 beta, which have been described to be sufficient to activate the IL-6 gene in other cell systems, shows a similar pattern of expression in both MCF-7 and MDA-MB-231 cells. Furthermore, transfection of a recombinant plasmid carrying the IL-6 promoter linked to a luciferase reporter gene shows that both cell lines are able to drive IL-1 beta or TNF-alpha activation of this construction in a very similar manner. Finally, when MCF-7 cells were treated with IL-1 beta or TNF-alpha in the presence of cycloheximide, transcription of IL-6 mRNA from the endogenous IL-6 gene was observed. These data suggest that a mechanism of IL-6 gene repression is active in MCF-7 cells.
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PMID:Nuclear factor kappa B (NF-kappa B), nuclear factor interleukin-6 (NFIL-6 or C/EBP beta) and nuclear factor interleukin-6 beta (NFIL6-beta or C/EBP delta) are not sufficient to activate the endogenous interleukin-6 gene in the human breast carcinoma cell line MCF-7. Comparative analysis with MDA-MB-231 cells, an interleukin-6-expressing human breast carcinoma cell line. 877 5

A patient with complaints of high fever and left shoulder pain was found to have a large mass in the left upper lobe on chest roentgenogram. Laboratory evaluation revealed marked thrombocytosis, hypoalbuminemia, and increased serum concentrations of CRP, fibrinogen and interleukin-6 (IL-6). A transcutaneous biopsy specimen revealed large cell carcinoma. Tumor production of IL-6 was confirmed by immunohistochemical staining with an anti-human IL-6 monoclonal antibody (MH60).
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PMID:Lung cancer producing interleukin-6. 878 56

A well-known metastic model of human oral cancer employs 9,10-dimethyl-1,2-benzanthracene (DMBA) to induce hamster cheek-pouch carcinoma. Streptococcal immunopotentiator OK432 was studied here for its inhibitory effect on lymph-node metastasis in that model. The intraperitoneal administration of OK432, after excision of cheek-pouch tumours induced by DMBA, resulted in a marked reduction in the incidence of cervical lymph-node metastasis to 7%, a significant decrease beneath the rates observed for control animals not receiving OK432 (40%). OK432 also caused an increased in serum levels of tumour necrosis factor-alpha and interleukin-6 in tumor-bearing hamsters. These results suggest that the immune response may play an important part in the antimetastatic effects of OK432.
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PMID:Inhibition by streptococcal immunopotentiator OK432 of lymph-node metastasis in hamster cheek-pouch carcinoma with enhancement of tumour necrosis factor-alpha and interleukin-6 in serum. 880 16

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.
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PMID:Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. 882 77

Prostate tumor cell lines have been shown to both produce interleukin-6 (IL-6) and express the IL-6 receptor, suggesting a potential autocrine growth regulatory role for IL-6. We explored the role of IL-6 in the proliferation of the human prostatic carcinoma cell line, DU145, using ribozymes to inhibit IL-6 expression. Hammerhead-type ribozymes targeted against IL-6 mRNA sequences were prepared, and in vitro analyses were used to demonstrate that these molecules catalyzed the cleavage of IL-6 mRNA poly- nucleotide fragments. To test in situ activity, these ribozymes were transfected into DU145 cells using cationic transfection lipids, cytofectins. Treatment of cultured cells with ribozyme/cationic lipid complexes resulted in a reduction of IL-6 protein levels in the supernatant and reduced numbers of DU145 cells 48 h after treatment. However, similar results were also seen following treatment with control RNA/lipid complexes. This reduction in IL-6 levels and cell numbers was a function of the RNA/lipid complexes and was not seen with either lipid or RNA alone. Therefore, the reductions in IL-6 levels and cell numbers observed were not due to ribozyme-mediated cleavage of IL-6 mRNA, but rather reflected a dose-dependent, nonspecific toxic effect of the treatment with ribozyme/cytofectin complexes. This effect can resemble functional ribozyme activity, complicating analysis of the activity of synthetic ribozymes after transfection into cultured cells.
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PMID:Toxicity of cationic lipid-ribozyme complexes in human prostate tumor cells can mimic ribozyme activity. 898 37

Hydrogen peroxide (H2O2) and some cytokines that are released during the inflammatory process are important factors for the development of urinary bladder carcinoma and for its growth. Sustained induction of H2O2-generating peroxisomal fatty acyl-CoA oxidase (ACOX) in the liver of rats and mice by non-genotoxic peroxisome proliferators leads to the development of liver tumors. To examine the role of intracellular H2O2 generated by ACOX during urinary bladder carcinogenesis, we overexpressed rat ACOX in a non-tumorigenic rat urothelial cell line, MYP3, under the control of the cytomegalovirus promoter. The clones overexpressing rat ACOX, when exposed to a fatty-acid substrate (150 microM linoleic acid), demonstrated strikingly higher levels of intracellular H2O2 (p > 0.001) and formed colonies in soft agar in proportion to the duration of exposure to linoleic acid. Furthermore, all the transformants, which were selected at random from soft agar, demonstrated an accelerated growth potential on a plastic surface, as well as tumorigenicity in athymic nude mice. In addition, the growth of these transformants was stimulated by cytokines, interleukin-6 and tumor necrosis factor-alpha, better than the growth of ACOX-overexpressing, but non-transformed cells or that of the parental cells. Our results clearly demonstrate that H2O2 induced by ACOX acts as a carcinogen on urothelial cells, and that transformed cells have acquired an advantage for growth over nonneoplastic cells because of their selective response to the stimulatory action of several cytokines.
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PMID:Tumorigenic conversion of a non-tumorigenic rat urothelial cell line by overexpression of H2O2-generating peroxisomal fatty acyl-CoA oxidase. 909 54

The cytolytic and anti-proliferative effects of bacillus Calmette-Guerin (BCG) and/or interferon-alpha-2b (IFN-alpha-2b) on 5 human bladder carcinoma cell lines, RT4, RT112, MGH, SD and J82, were determined. The cell lines showed different sensitivities to BCG and IFN-alpha-2b. BCG had direct dose-dependent cytolytic and anti-proliferative effects on MGH, J82 and SD (grade 3 cell lines), whereas RT4 and RT112 (grades 1 and 2, respectively) were less sensitive. Surprisingly, higher concentrations of BCG enhanced cell growth of RT4. IFN-alpha-2b also had cytolytic and anti-proliferative effects on all 5 cell lines. Thus, the RT4 and RT112 cell lines that were not sensitive to BCG were highly sensitive to IFN-alpha-2b. A combination of BCG and IFN-alpha-2b had additive anti-proliferative effects on MGH, J82 and RT112. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production by these 5 cell lines was measured after stimulation with BCG and/or IFN-alpha-2b, by ELISA immunoassays. Production of IL-6 and TNF-alpha was significantly increased in MGH and J82 cell lines by the combination of BCG and IFN alpha-2b. The enhanced cytolytic and anti-proliferative effects of the combination of BCG and IFN-alpha-2b may be related to the induction of cytokines.
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PMID:Effects of bacillus Calmette-Guerin and interferon-alpha-2B on human bladder cancer in vitro. 918 Jan 56

Cytokines are low-molecular-weight protein mediators that possess a wide spectrum of inflammatory, metabolic, and immunomodulatory properties. Cytokines have been shown to be produced by monocytes/macrophages, lymphocytes, fibroblasts, endothelial cells, and more recently, hepatocytes and biliary epithelium. The aim of this study was to define biliary levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) in various disease states. Fifty-four patients undergoing ERCP comprised the study group. IL-6 and TNF-alpha were measured in aspirated bile using an ELISA technique. Levels of both TNF-alpha and IL-6 were significantly higher in patients with cholangitis (P < 0.00001). Moreover, IL-6 was 100% specific for cholangitis since none of the patients without bacterial cholangitis-including patients with biliary obstruction secondary to cholangiocarcinoma or pancreatic carcinoma-had measurable IL-6 in their bile. Low levels of biliary TNF-alpha were detectable in five patients without cholangitis; the sensitivity and specificity of TNF-alpha for cholangitis were 100% and 82%, respectively. There was a strong statistical correlation between biliary IL-6 and TNF-alpha levels (r = 0.819, P < 0.0001). In contrast, the correlations between biliary cytokines and serum biochemical parameters were weak. These results suggest that IL-6 and TNF-alpha are sensitive markers for cholangitis and may differentiate it from other types of biliary tract disease.
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PMID:Biliary interleukin-6 and tumor necrosis factor-alpha in patients undergoing endoscopic retrograde cholangiopancreatography. 920 Oct 97

Met and ron proto-oncogenes encode the cell surface receptors for hepatocyte growth factor (HGF) and hepatocyte growth factor-like (HLP) protein, respectively, and induce mitogenesis, motogenesis, morphogenesis, and metastatic activity in various cell types. Overexpression of met in human carcinoma has been reported by several groups including ours; however, the mechanisms that control met gene expression are thus far unclear. The present study focuses on the expression and regulation of the Met and Ron receptors in human hepatocellular carcinoma (HCC). We report here that abnormal expression of met and ron proteins occurs in some cases of human HCC. Using several HCC cell lines as a model system, we show that HGF, as well as other cytokines, such as epidermal growth factor (EGF), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), induce met and ron expression. Using several chimeric constructs consisting of various lengths of the met promoter region fused to the reporter gene of chloramphenicol acetyl transferase (CAT), and by performing transient transfection of these constructs into HepG2 cells, we show that induction of met gene expression by HGF and other cytokines is, at least in part, through up-regulation of met gene promoter activity. The DNA region conferring responsiveness to cytokine induction was located within 0.2 kb of the met core promoter. Interestingly, EGF did not stimulate met promoter activity in any of the met-CAT chimeric constructs. These results provide evidence that met and ron are modulated in the liver by a similar cytokine network. In the case of met expression, the 0.2-kb region in the met gene promoter may play an important role in mediating its gene induction in response to HGF and other cytokines. Our results also suggest that unregulated expression of met and ron may be associated with pathological conditions, such as HCC, in the liver.
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PMID:Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. 921 52

Metastasis of pancreas carcinoma to the liver via the portal vein carries the gravest prognosis to patients. Using 10 cultured lines of pancreas carcinoma (PCI), established in our laboratory, we examined phenotypes that are important in hematogenous metastasis to the liver in anti-asialo GM1 treated nude mice. IL-6 production by PCI lines inversely correlated with liver metastasis, indicating that tumor-derived IL-6 may modulate metastatic competence. Therefore, we transfected human interleukin-6 cDNA in combination with the cytomegalovirus promoter to the non-IL-6 producer PCI-43, the line with the highest metastatic potential. Thus we established interleukin-6 high-, low-, and non-producer PCI-43, variant lines. Transfection itself did not endow PCI-43 line with alterations in surface phenotypes, kinesis, invasiveness, and doubling time in vitro. Metastatic potential of PCI-43 was profoundly suppressed in IL-6 high producer sublines. In mice inoculated with IL-6 high-producer PCI-43, an increase in human IL-6 in sera, as well as an appearance of PCI-43-reactive IgG was seen. The reduction in metastasis, therefore, may be mediated by antibody-dependent or complement-dependent cytotoxicity.
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PMID:[The effect of IL-6 produced by pancreatic carcinoma cells on blood-borne metastasis to the liver: a study on in vivo nude mouse model]. 937 58


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