Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncostatin M (OSM) and other members of the interleukin-6 cytokines, like ciliary neurotrophic factor and leukemia inhibitory factor, can induce differentiation of glial cells. We have recently described that OSM inhibited the growth of human glioma cells in vitro and induced a cell morphology resembling that of mature astrocytes. Using the glioblastoma cell line 86HG39, we demonstrated that treatment of the glioma cells with OSM also leads to a differentiation of the malignant glioma cells as judged by a strong increase in glial fibrillary acidic protein expression. The differentiation and the growth inhibition were not significantly blocked by expression of a dominant-negative (dn) signal transducer and activator of transcription (Stat) 3 protein. OSM exerted a reduction in DNA synthesis even in the presence of a high expression level of dnStat3. Moreover, inhibition of the ras-raf-mitogen-activated protein kinase (MAPK) pathway by the MAPK kinase 1 inhibitor PD98059 resulted in a synergistic enhancement of the OSM effect, indicating that the activation of this pathway counteracts the activity of the cytokine.
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PMID:Oncostatin M-mediated growth inhibition of human glioblastoma cells does not depend on stat3 or on mitogen-activated protein kinase activation. 1093 78

Interleukin-6 (IL-6) is a B-cell differentiating and T-cell activating cytokine that is expressed in T cells, neutrophils, monocytes, macrophages, and mast cells. Because IL-6 is also synthesized and released by anterior pituitary cells and IL-6 stimulates pituitary hormone release, this cytokine may serve a paracrine or autocrine role within the pituitary. Interleukin-1 beta (IL-1 beta) stimulates IL-6 release from anterior pituitary cells through a mechanism that involves lysophosphatidylcholine (LPC 18:0) generation and protein kinase C activation. In the rat C6 glioma cell line, IL-1 beta synergistically stimulates IL-6 release in the presence of increased intracellular cAMP concentrations. The catecholamines and serotonin also synergistically stimulate IL-6 release in the presence of IL-1 beta. LPC 18:0 synergistically increases IL-6 release in the presence of norepinephrine, and IL-1 beta transiently increases LPC 18:0 formation in C6 cells. Therefore, IL-1 beta induction of LPC 18:0 may lead to increases in IL-6 production via activation of a kinase cascade. The bovine thymic preparation, thymosin fraction 5 (TF5), also stimulates IL-6 release from C6 glioma cells in a protein kinase C-dependent manner. Of interest, TF5 inhibits the proliferation of C6 cells, pituitary adenoma MMQ cells, and promyelocytic HL-60 cells. We suggest that a thymic hormone immune surveillance mechanism may suppress neuroendocrine and hematopoietic tumor formation. Thus, IL-1 beta and certain thymic peptides act to increase IL-6 expression in neuroendocrine cells. The enhanced production of neuroendocrine cytokines may affect hormone secretion, neurotransmission, and the development of certain neurodegenerative disorders (e.g., Alzheimer's disease). The isolation of the active component of TF5 that inhibits neuroendocrine and hematopoietic tumor cell proliferation will provide a potential therapeutic strategy for the treatment of these tumors.
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PMID:Interleukin-1 beta and thymic peptide regulation of pituitary and glial cell cytokine expression and cellular proliferation. 1126 88

Most tumors, including gliomas, are resistant to tumor necrosis factor (TNF) cytotoxicity unless protein or RNA synthesis is inhibited. We investigated the effects of the combined use of TNF-alpha and cisplatin (CDDP) on cultured malignant glioma cells, T98G, U373MG, A172, and U87MG. All glioma cell lines were sensitive to treatment with CDDP but resistant to TNF-alpha during 24 h-incubation. The combined use of CDDP and TNF-alpha had synergistic effects on T98G and U87MG but not on U373MG and A172 cells. Sequential treatments showed that only pretreatment with CDDP for 2 h followed by TNF-alpha for 22 h was synergistic on cell cytotoxicity. Annexin V-flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling assay showed that TNF-alpha can induce apoptosis in cells treated with CDDP. Although only sensitive cell lines express transcripts for p75 TNF receptor 2, changes in TNF receptors were not found to contribute to the susceptibility to TNF-alpha. The production of interleukin-6, a representative cytoprotective cytokine, from glioma cells stimulated by TNF-alpha was suppressed by the combined use of actinomycin D, but not CDDP. Our results indicate that CDDP can sensitize glioma cells to TNF-alpha-induced apoptosis by a mechanism other than blocking the cytoprotective protein production.
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PMID:Sensitization of human malignant glioma cell lines to tumor necrosis factor-induced apoptosis by cisplatin. 1145 Dec

The abnormal vascular system of brain cancers inappropriately expresses membrane proteins, including proteolytic enzymes, ultimately resulting in blood extravasation. The production of inflammatory mediators, such as cytokines and nitric oxide, and tumor hypoxia have been implicated in these effects. We have previously shown that the activity of aminopeptidase A is increased in the abnormal vascular system of human and rat brain tumors. To study the mechanisms regulating the activities of peptidases in cerebral vasculature in brain tumors, we have developed a three-dimensional model of differentiated rat brain cells in aggregate cultures in which rat brain microvessels were incorporated. The secretion of interleukin-6 (IL-6) in the culture medium of aggregates was used as an indicator of inflammatory activation. Addition to these aggregates of C6 glioma cell medium (C6-CM) conditioned under hypoxic or normoxic conditions or serum mimicked tumor-dependent hypoxia or conditions of dysfunction of brain tumor vasculature. Hypoxic and normoxic C6-CM, but not serum, regulated peptidase activity in aggregates, and in particular it increased the activity of aminopeptidase A determined using histoenzymography. Serum, but not C6-CM, increased IL-6 production, but did not increase aminopeptidase A activity in aggregates. Thus soluble glioma-derived factors, but not serum-derived factors, induce dysfunctions of cerebral vasculature by directly regulating the activity of peptidases, not involving inflammatory activation. Tumor hypoxia is not necessary to modulate peptidase activity.
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PMID:Regulation of peptidase activity in a three-dimensional aggregate model of brain tumor vasculature. 1248 84

The pleiotropic cytokine interleukin-6 (IL-6) contributes to malignant progression and apoptosis resistance of various cancer types. Although IL-6 is elevated in malignant gliomas, and glioma cells respond to IL-6, its functional role in gliomagenesis is unclear. We have investigated this role of IL-6 in a mouse model of spontaneous astrocytoma by crossbreeding glial fibrillary acidic protein (GFAP)-viral src oncogene transgenic mice with IL-6-deficient mice. We show here that ablation of IL-6 prevents tumour formation in these predisposed animals, but did not affect preneoplastic astrogliosis. Moreover, we demonstrate phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription (STAT)3, a prerequisite for IL-6 signalling, in 51 human gliomas WHO grade II-IV and all experimental mouse tumours investigated. Together with the observation that STAT3 activation increases with malignancy, these findings indicate an important role for IL-6 in the development and malignant progression of astrocytomas.
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PMID:IL-6 is required for glioma development in a mouse model. 1506 29

Regulation of astrocyte differentiation is a key process in the development of the central nervous system (CNS), and disturbance of the differentiation can lead to brain system dysfunction. Here we show that beta-naphthoflavone (betaNF), an agonist of the aryl hydrocarbon receptor (AhR), disturbed the cAMP-induced astrocytic differentiation of C6 glioma by inhibiting autocrine interleukin-6 (IL-6). Treatment of cells with betaNF reduced the induction of an astrocyte marker glial fibrillary acidic protein (GFAP). This was caused by the inactivation of its upstream transcription factor signal transducer and activator of transcription 3 (STAT3) by betaNF. In addition, betaNF attenuated the induction of the IL-6 gene, which leads to the activation of STAT3. Most importantly, the inhibitory effect of betaNF on GFAP promoter activity was recovered by the addition of recombinant IL-6. Taken together, these results indicate that the inhibitory effect of betaNF on IL-6 induction suppresses STAT3 activation. These processes subsequently lead to the attenuation of GFAP induction.
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PMID:Beta-naphthoflavone disturbs astrocytic differentiation of C6 glioma cells by inhibiting autocrine interleukin-6. 1525 54

The splicing of many alternative exons in the precursor messenger RNA (pre-mRNA) is regulated by extracellular factors but the underlying molecular bases remain unclear. Here we report the differential regulation of Bcl-x pre-mRNA splicing by extracellular factors and their distinct requirements for pre-mRNA elements. In K562 leukemia cells, treatment with interleukin-6 (IL-6) or granulocyte-macrophage colony stimulating factor (GM-CSF) reduced the proportion of the Bcl-xL variant mRNA while treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) had no effect. In U251 glioma cells, however, TPA efficiently increased the Bcl-xL level. These regulations were also seen for a transfected splicing reporter mini-gene. Further analyses of deletion mutants indicate that nucleotides 1-176 on the downstream intron are required for the IL-6 effect, whereas additional nucleotides 177-284 are essential for the GM-CSF effects. As for the TPA effect, only nucleotides 1-76 are required in the downstream intron, Thus UK-6, GM-CSF and TPA differentially regulate Bcl-x splicing and require specific intronic pre-mRNA sequences for their respective effects.
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PMID:Regulation of alternative splicing of Bcl-x by IL-6, GM-CSF and TPA. 1562 14

Interleukin-6 (IL-6) expression is strongly correlated with the degree of human glioma malignancy and necessary for tumor formation in a mouse model of spontaneous astrocytomas. Yet, exactly how IL-6 contributes to malignant progression of these brain tumors is still unclear. We have scrutinized the mechanism of transcriptional activation of vascular endothelial growth factor (VEGF) expression by IL-6 in the mouse brain and in glioblastoma cells. We demonstrate here that IL-6 drives transcriptional upregulation of VEGF in astrocytes in vivo using glial fibrillary acidic protein (GFAP)-IL-6/VEGF-green fluorescent protein (GFP) double transgenic mice. We further show that IL-6-induced VEGF transcription and VEGF secretion by human glioblastoma cells is dependent on signal transducer and activator of transcription 3 (STAT3). By progressive 5'-deletion analysis we defined the minimal VEGF promoter region for IL-6-responsiveness to nucleotides -88/-50. Surprisingly, this promoter region is rich in GC-boxes and does not contain STAT3 binding elements. Electrophoretic mobility shift and supershift assays revealed binding of Sp1 and Sp3 to the -88/-50 element upon IL-6 stimulation. Interestingly, preincubation with STAT3 antibody prevented the binding of Sp1 and Sp3 to the -88/-50 element, indicating that STAT3 is involved in IL-6-driven Sp1/Sp3 protein-DNA complex formation. Physical interaction of STAT3 and Sp1 was demonstrated by coimmunoprecipitation. The functional relevance of the STAT3/Sp1 association was corroborated by transient transfection experiments, which showed that overexpression of constitutively active STAT3 increased the minimal VEGF promoter activity. Taken together, our study suggests that IL-6 promotes tumor angiogenesis in gliomas and describes a novel transcriptional activation mechanism for STAT3 in the context of a STAT3 binding element (SBE)-free promoter.
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PMID:Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. 1568 1

Cp is an acute phase reactant protein that also acts as a ferroxidase, and thus indirectly decreases the production of the reactive oxygen species hydroxyl radical. Ceruloplasmin (Cp) expression is induced by a variety of central nervous system injuries, but the mechanism by which this occurs is unclear. Based on the fact that peripheral nerve injury induces interleukin-6 (IL-6) expression and that there are three IL-6 response elements in the upstream region of the Cp gene, we studied their role in transcriptional regulation of Cp in astrocytic C6 glioma cells, using transfection of a rat Cp-luciferase construct, followed by sequential and simultaneous mutation of the IL-6 response elements. We found that 0.8 kb of sequence upstream to the rat ceruloplasmin start site was sufficient to drive luciferase expression in C6 glioma cells. Cells transfected with Cp-luc and treated with 100 ng/ml rat IL-6 induced 216.8% +/- 4.6% of control activity. Mutagenesis of the IL-6 response elements decreased luciferase activity, with the maximal decline (9.7 +/- 0.7% of wild-type) after mutation of the second site. Mutagenesis of multiple sites decreased activity beyond mutagenesis of single sites with mutation of all three sites decreasing activity to 5.3 +/- 0.4% of wild-type. Gel shift and supershift assays indicated that activation of Cp in these cells was not via STAT-3. These results are consistent with a signaling process via IL-6 response elements for Cp upregulation.
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PMID:Transcriptional regulation of ceruloplasmin by an IL-6 response element pathway. 1597 98

Interleukin-6 (IL-6) is known to promote tumour growth and survival. We evaluated IL-6 gene amplification in tumours from 53 glioma patients using fluorescence in situ hybridisation. Amplification events were detected only in glioblastomas (15 out of 36 cases), the most malignant tumours, and were significantly associated with decreased patient survival.
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PMID:Interleukin-6 gene amplification and shortened survival in glioblastoma patients. 1722 23


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