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)

Multiple myeloma (MM) originates from the malignant clonal expansion of transformed B-lymphocytes (in which c-myc and ras oncogenes are probably involved). MM cells have a hybrid phenotype (with coexpression of the markers for both early and late B-differentiation and, sometimes, of T-lymphocyte, myelomonocyte, erythroid and megakaryocyte markers), which accounts for the association between MM and myeloproliferative disorders and for cytokine production. Interleukin-6 and immunologic control mechanisms regulate proliferation and differentiation into plasma cells secreting a monoclonal component (MC). Overt MM is diagnosed 1-2 years following malignant transformation. At this time, several aneuploid clones with resistant phenotype have been selected, and a small pool of actively cycling cells produces the great bulk (over 90%) of non proliferating tumor cells. The clinical and laboratory signs of MM arise from both tumor proliferation and MC damage to organs and organ systems. Tumor proliferation is mainly responsible for bone disease (since MM cells produce cytokines that activate the osteoclasts), inhibition of hemopoiesis and the appearance of plasma cell tumors. The MC causes renal failure, neurological signs, hemorrhagic manifestations. The prognosis for multiple myeloma is probably best estimated by two parameters, serum beta-2-microglobulin and the bone marrow labeling index. Induction therapy is still based on the use of alkylating agents, melphalan and cyclophosphamide, combined with prednisone. Second line treatment consists of VAD polychemotherapy or high-dose pulsed glucocorticoids. Many investigational approaches have been proposed, but their effectiveness awaits confirmation. In the absence of a curative regimen, much effort should be dedicated to the quality of supportive care. In this respect, bisphosphonates represent a new effective tool for the control of myeloma bone disease.
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PMID:Multiple myeloma. 208 Oct 91

The effects of interleukin-6 (IL-6), a cytokine recently found to be secreted by monocytes and macrophages, on c-myc expression and proliferation of cultured vascular smooth muscle cells (VSMC) were investigated. Treatment with IL-6 caused rapid increase in the c-myc mRNA level of VSMC. It also stimulated DNA synthesis and proliferation of the cells significantly and dose-dependently at concentrations of more than 10 U/ml. These results suggest that IL-6 may be important in the proliferation of VSMC, which is a key event in the development of arteriosclerosis, as a factor mediating immune cell-VSMC interaction.
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PMID:Interleukin-6 stimulates c-myc expression and proliferation of cultured vascular smooth muscle cells. 234 97

It has been demonstrated that interleukin-6 (IL-6) is a cytokine regulating immune response, acute-phase reaction and hematopoiesis. The deregulated expression of IL-6 was suggested to be actually involved in the pathogenesis of polyclonal B cell activation and autoimmune diseases such as rheumatoid arthritis. It could be hypothesized that continuous polyclonal B cell activation may be eventually leading to the generation of plasmacytoma/myeloma, possibly with additional expression of oncogene(s) such as c-myc gene. Therefore, future studies on the gene regulation of IL-6 would provide critical informations on the molecular pathogenesis of these diseases. Furthermore, IL-6 could be used as anti-cancer drug in certain tumors. Moreover, inhibitors of IL-6 such as anti-IL-6 monoclonal antibodies or soluble forms of IL-6 receptors could be useful in the treatment of such polyclonal/monoclonal B cell abnormalities.
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PMID:Interleukin-6: possible implications in human diseases. 266 8

Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) share a signal-transducing molecule called gp130. Previous studies showed that CNTF regulates fibrinogen gene expression in rat hepatocytes by competitive binding to the IL-6 receptor. This report explores the post ligand-binding events in the control of fibrinogen and early response gene production stimulated by IL-6 and CNTF in primary rat hepatocytes. Metabolic labeling, using [32P]orthophosphate or anti-phosphotyrosine antibody (Ab) blot experiments revealed that both IL-6 and CNTF induced tyrosine phosphorylation of gp130, and the Jak1 and Jak2 kinases in a dose- and time-dependent manner. Additional experiments revealed that only one of the early response genes, junb, but not c-myc or c-fos, was stimulated by the addition of either IL-6 or CNTF. These data suggest that activation of Jak kinases and stimulation of junb reflect a divergence of the IL-6/CNTF signaling pathway and further suggest that junb may participate in cytokine control of acute-phase protein production in the inflammatory response.
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PMID:Interleukin-6 and ciliary neurotrophic factor trigger janus kinase activation and early gene response in rat hepatocytes. 755 45

Epidemiologic data indicate the crucial role of chronic hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development. On the molecular level, HBV sequences are frequently integrated in hepatocellular DNA. However, in contrast to the woodchuck model, in which specific HBV-DNA integration is detectable in most cases, insertional (in-) activation of cellular genes seems to be a rare event in man. The recent discovery of transactivating functions exerted by HBx and truncated HBs(urface) proteins supports the notion that transactivation of cellular gene expression could be relevant to hepatocarcinogenesis. HBV transactivator sequences are present in 81% (21/26) of HCC tissues or hepatoma-derived cell lines. At least one transactivator protein was functional in all cases investigated so far. The 16.5-kDa HBx transactivator has been shown to stimulate gene expression from various cellular target sequences. In vitro, HBx displays oncogenic potential. A second type of transactivator is encoded in the preS/S region of HBV. In contrast to HBx, HBs transactivators require carboxyterminal truncation to gain their transactivating function. Unlike full-length M(iddle)HBs, the truncated MHBst is retained in the endoplasmic reticulum and not secreted into the surrounding medium. Cellular gene expression is stimulated by regulatory elements of the human proto-oncogenes c-fos and c-myc, as well as by the hepatic acute-phase interleukin-6 gene. Synthetic binding sites for the transcription factors NF-kappa B, AP-1, AP-2, SRE, and Sp1 render minimal promoters activatable. NF-kappa B-mediated transactivation by MHBst can be suppressed by radical scavenging antioxidants, indirectly suggesting that reactive oxygen intermediates are involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. 760 73

Tumors obtained from v-Ha-ras-transformed PB-3c cells are characterized by autocrine interleukin-3 (IL3) expression, which occurs either without (class I tumors) or with enhanced transcription (class II tumors). To address possible post-transcriptional mechanisms of IL3 expression, IL3 mRNA stability was examined in both tumor classes. Increased stability of IL3 mRNA was detected in class I tumor lines (t1/2 > 3 h), whereas rapid decay of IL3 transcripts (t1/2 < 0.5 h) was found in class II tumor lines. In both tumor classes, the c-myc and interleukin-6 transcripts were short-lived. Transcripts of a constitutively expressed IL3 reporter gene were stable in class I tumor cells but unstable in class II tumor cells, suggesting that IL3 mRNA stabilization involved a trans-acting mechanism. Rapid decay of IL3 reporter transcripts was observed in untransformed PB-3c as well as in v-Ha-ras expressing precursor cells linking transcript stabilization to the tumor stage. Reporter transcript stabilization in class I tumor cells correlated with increased IL3 production. Deletion of the AU-rich element from the IL3 reporter gene further augmented IL3 mRNA levels as well as IL3 production, suggesting that the stabilizing mechanism in class I tumor cells is not equivalent to AU-rich element deletion.
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PMID:Interleukin-3 mRNA stabilization by a trans-acting mechanism in autocrine tumors lacking interleukin-3 gene rearrangements. 765 42

Transcription factor E2F binds to cellular promoters of certain growth- and cell cycle-controlling genes and forms distinct heteromeric complexes with other nuclear proteins. We show here that alpha and beta interferons (alpha, beta) and interleukin-6 abolished the E2F-containing DNA-binding complexes in Daudi Burkitt lymphoma cells and in M1 myeloblastic cells, which responded to the cytokines by suppression of c-myc transcription. Time kinetics studies showed that the abolishment of E2F complexes coincided with reduction of c-myc expression and that both molecular events preceded the cell cycle block in G0/G1 phase. In contrast, the pattern of E2F complexes remained unchanged in an interferon-treated growth-resistant Daudi cell mutant that displayed relaxed regulation of c-myc. All of the DNA-binding E2F complexes, including those containing the retinoblastoma protein (pRB), cyclin A-p33cdk2, and the free forms of E2F, were reduced by interferons or interleukin-6. Their abolishment was unperturbed by pharmacological treatments that alleviated the cyclin A and pRB responses to interferon. Thus, changes in cyclin A expression and pRB phosphorylation are not primary events that influence the pattern of E2F responses to cytokines. Addition of EDTA to cell extracts of interferon-treated Daudi cells restored the DNA-binding activity of E2F, resulting in the appearance of a single E2F complex that exclusively contained pRB. It is suggested that the regulation of E2F by growth-inhibitory cytokines that induce cell cycle exit takes place at the level of the DNA-binding activity, and by that mean it differs basically from the phase-specific regulation of E2F in cycling cells.
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PMID:Interferons and interleukin-6 suppress the DNA-binding activity of E2F in growth-sensitive hematopoietic cells. 768 48

In order to enhance recombinant protein productivity in animal cells, we developed the oncogene activated production (OAP) system. The OAP system is based on the premise that oncogenes are able to enhance promoter activity. To this end, we constructed reported plasmids by fusing various promoters to the human interleukin-6 (hIL-6) cDNA, and the effector plasmids by inserting individual oncogenes, for example c-myc, c-fos, v-jun, v-myb and c-Ha-ras, downstream from the human cytomegalovirus immediate early (CMV) promoter. Results of transient expression experiments with BHK-21 cells suggest that the CMV promoter is the most potent promoter examined and that the ras product is able to transactivate the beta-actin, CMV and SR alpha promoters. Recombinant BHK-21 cells producing hIL-6 under the control of the CMV promoter were contransfected with the ras oncogene and dihydrofolate reductase gene, then selected with 50 nM methotrexate to coamplify the ras oncogene. We were able to rapidly establish a stable and highly productive clone which exhibited a 35-times higher production rate as compared to the control value.
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PMID:Ras oncogene enhances the production of a recombinant protein regulated by the cytomegalovirus promoter in BHK-21 cells. 776 45

Stable transfection of M1 myeloid leukemia cells with a temperature-sensitive mutant of p53 results in two phenomena that are manifested exclusively at the permissive temperature. On one hand, activation of wild-type p53 by the temperature shift induced an apoptotic type of cell death which could be inhibited by interleukin-6 (IL-6) (E. Yonish-Rouach, D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Nature 352:345-347, 1991). On the other hand, as reported in this work, activated p53 complemented the antiproliferative effects of IL-6 in M1 cells. A shift to the permissive temperature concomitant with or early after IL-6 treatment imposed a novel pattern of cell cycle arrest in which about 95% of the cells were retained within a G0-like quiescent state. This phase was characterized by 2N DNA content and low RNA and protein content. On the molecular level, activation of wild-type p53 transrepressed the c-myc gene but not the cyclin A, D1, or D2 gene, which are all independently suppressed by IL-6 in M1 cells. To further analyze whether c-myc inhibition mediates or complements p53 effects, the p53-transfected M1 cells were infected with a retroviral vector expressing deregulated c-myc, refractory to p53 or IL-6 action. It was found that the process of cell death was not interrupted at all in these M1 c-myc-p53 double transfectants, suggesting that the transrepression of c-myc is not a major obligatory event mediating p53-induced cell death. In addition, some of the antiproliferative effects of activated p53, manifested in the presence of IL-6, could still be transmitted in the background of constitutive c-myc. Yet the context of deregulated c-myc interfered with the final accumulation of cells within a G0-like phase, suggesting complementary interactions between the outcome of p53 activation and of c-myc suppression in the control of cell cycle arrest.
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PMID:Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression. 824 9

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


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