UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat C6 glioma synthesizes a low basal level of interleukin-6 (IL-6). Stimulation with 10 micrograms/ml of lipopolysaccharide (LPS) and induction of differentiation with 1 mM N6,O2'-dibutyryl cyclic AMP (dbcAMP) for 48 h increased the secreted activity to 400 and 800 U/ml, respectively. An LPS stimulation of dbcAMP-differentiated cells strongly enhanced the secreted activity. Depending on the dbcAMP concentration, the cell number, and the stimulation time, the secreted IL-6 level increased up to 120,000 U/ml. After 48 h of costimulation with 10 micrograms/ml of LPS and 1 mM dbcAMP, northern blotting and immunoassay demonstrated an eightfold increase in IL-6 mRNA concentration and IL-6 immunoreactivity, whereas titration of the biological activity indicated a 100-fold increase in the secreted IL-6 activity. The enhanced secretion of IL-6 is correlated with the induction of differentiation. Chromatography on heparin-Sepharose and on DEAE-5PW separated the secreted activity into several fractions, indicating that they differ in heparin affinity and charge either by posttranslational modifications or by binding to a carrier protein. Each of the partially purified IL-6-like activities could be neutralized by an anti-murine IL-6 antibody. Our observations demonstrate that in vivo inflammatory signals can trigger astrocytes and their precursors to secrete substantially different levels of immunoregulatory cytokines depending on their degree of differentiation.
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PMID:Lipopolysaccharide-enhanced expression of interleukin-6 in dibutyryl cyclic AMP-differentiated rat C6 glioma. 859 15

The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to abrogate chemotherapy-induced neutropenia has become a routine part of many cancer treatment regimes. However, there are still very few data available about possible complications related to repeated or prolonged use of these agents in patients with malignant solid tumors. The authors report a child with brainstem glioma who received repeated cycles of multiagent chemotherapy with G- or GM-CSF support. During this period of 10 months, no clinical side effects were observed that could have been attributed to growth factor administration. However, postmortem histological examination revealed the presence of diffuse plasmacytosis, a rare hematological disorder in childhood. Undifferentiated plasma cells of nonmonoclonal origin could be demonstrated infiltrating bone marrow, lungs, and lymph nodes of the patient. Based on previously published in vitro and in vivo evidence on the interleukin-6 (IL-6)-mediated stimulatory effect of G- and GM-CSF on myeloma cell proliferation, the authors suggest a possible link between extensive growth factor support and the development of plasmacytosis in this patient.
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PMID:Diffuse plasmacytosis in a child with brainstem glioma following multiagent chemotherapy and intensive growth factor support. 861 71

Glia cell line-derived neurotrophic factor (GDNF), a recently cloned member of the transforming growth factor-beta (TGF-beta) superfamily, has been implicated in the survival, morphological and functional differentiation of midbrain dopaminergic neurons and motoneurons in vitro and in vivo. The factor may thus have utility in the treatment of various human neurodegenerative disorders. Mechanisms regulating expression of GDNF in normal and diseased brain as a possible means to increase the local availability of GDNF are only beginning to be explored. We have established and employed a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to study and compare levels of expression of GDNF mRNA in several cell types and to investigate its regulation. GDNF expression was clearly evident in primary cultured astrocytes, the glioma B49 and C6 cell, but less pronounced in the Schwannoma RN22 cell lines. Little or no signal could be observed in neuroblastoma cell lines (IMR32, LAN-1) or the pheochromocytoma cell line PC12, emphasizing the glial character of this factor. Using the C6 cell line we found that fibroblast growth factor-2 (FGF-2; bFGF) can increase GDNF mRNA levels, whereas FGF-1, platelet-derived growth factor (PDGF), and vasoactive intestinal polypeptide (VIP) are apparently ineffective. Several other factors (forskolin, kainic acid, triiodothyronine dexamethasone, GDNF, TGF-beta 1, and interleukin-6) appear to have slightly negative effects on GDNF mRNA levels at the concentrations tested. To further explore the relationship between FGF-2 and GDNF, we also addressed the question whether GDNF, like FGF-2, may have an effect on C6 cell proliferation. We conclude that (1) glial and glial tumor cells, rather than neuronal cell lines, express GDNF, (2) that FGF-2 has a prominent inductive effect on GDNF expression and (3) that GDNF stimulates C6 cell proliferation. Finally, these data suggest that neurotrophic actions of FGF-2 in mixed glial-neuronal cell cultures might be mediated in part by GDNF.
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PMID:GDNF mRNA levels are induced by FGF-2 in rat C6 glioblastoma cells. 888 50

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a seco-steroid hormone with potential antitumoral activities, has been recently reported to exert cytotoxic effects on C6 glioma cells. However, the molecular mechanisms which trigger this cell death remain unknown. We show here that this 1,25(OH)2D3-induced cell death is dependent upon protein synthesis and is accompanied by the expression of c-myc, p53, and gadd45 genes. Two other genes, coding for interleukin-6 and vaso-endothelial growth factor, are also upregulated after addition of 1,25(OH)2D3. This programmed cell death can be suppressed when cells are treated with forskolin, a drug which increases intracellular cAMP concentration, or with genistein, an inhibitor of tyrosine protein kinases. However, in spite of the demonstration of fragmented DNA in 1,25(OH)2D3-treated cells, the C6.9 cells used in this study do not show the classical morphological features of apoptosis. These results provide the first evidence for the existence of a programmed cell death triggered by 1,25(OH)2D3 in glioma cells and may provide a basis for the development of new therapeutic strategies. In addition, these data also suggest that the treatment of C6.9 cells with 1,25(OH)2D3 may be a useful model to study the molecular mechanisms involved in the programmed cell death of a cell of glial origin.
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PMID:1,25-Dihydroxyvitamin D3 induces programmed cell death in a rat glioma cell line. 895 66

Thymosin fraction 5 (TF5) is a partially purified preparation of the bovine thymus possessing immunopotentiating properties. TF5 also stimulates the hypothalamic-pituitary-adrenal axis in vivo and anterior pituitary hormone release in vitro. Interleukin-6 (IL-6) is an inflammatory, pyrogenic cytokine that also stimulates hypothalamic and anterior pituitary hormone release. We hypothesized that TF5 may activate the neuroendocrine system in part via the stimulation of central cytokine production. Therefore, we determined the effects of TF5 on IL-6 release from rat C6 glioma cells in vitro. Glioma cells (25-100 x 10(3)) were exposed to vehicle (RPMI-1640) or TF5 (10-1,000 micrograms/ml) in 96-well plates (200 microliters incubation volume) for 4-24 h to determine optimal cell number and incubation period conditions. TF5 (1,000 micrograms/ml) stimulated IL-6 release from 100 x 10(3) C6 cells/well by 9-fold following a 24-hour incubation (p < 0.01). Reducing the number of cultured C6 cells to either 50 or 25 x 10(3) cells/well resulted in diminished IL-6 responses to TF5. TF5 stimulated C6 cell IL-6 release in a time-dependent manner (4-24 h) at all concentrations tested. A 24-hour incubation period provided the largest TF5-stimulated increases in IL-6 release compared with shorter time intervals (i.e., 4-8 h). Pretreatment of C6 glioma cells with 1 microM phorbol myristate acetate (PMA) for 24 h completely blocked the subsequent stimulation of IL-6 release by PMA (20-250 nM) and partially blocked by 50% the TF5 stimulation of this cytokine. Peptides previously purified from TF5 had no effect on IL-6 release at 50-1,000 nM [i.e., thymosin alpha 1 (T alpha 1), thymosin beta 4 (T beta 4), MB35, MB40]. Therefore, TF5 was further fractionated into 7 pools by preparative reverse phase high performance liquid chromatography (HPLC). HPLC pools P1 (fractions 1-8) and P2 (fractions 9-12) significantly increased C6 cell IL-6 release (p < 0.01) to the same extent as 250 micrograms/ml TF5. Other HPLC pooled fractions (P3-P7) had no effect on IL-6 release from C6 glioma cells. P1 and P2 stimulated a 50- and 10-fold increase in IL-6 release, respectively, at a protein concentration of 1.0 microgram/ml. Therefore, P1 was more potent and displayed a greater efficacy for the stimulation of IL-6 release compared to P2. Analysis of individual fractions of P1 and P2 revealed that 1 microgram/ml of fraction 6 was as efficacious as 250 micrograms/ml TF5 for the stimulation of IL-6 release. These data indicate that one or more peptide components of TF5 enhance glial cell production of IL-6. In addition, the thymosin-stimulated production of extracellular IL-6 is mediated partially by one or more isoforms of protein kinase C. We hypothesize that a peptide product of the thymus transported across the CNS blood-brain barrier may stimulate the glial cell production of IL-6 and affect neuronal, neuroendocrine and/or inflammatory processes.
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PMID:A novel thymosin peptide stimulates interleukin-6 release from rat C6 glioma cells in vitro. 950 Jan 50

The neuropoietic cytokines of the interleukin-6 family are a group of structurally and functionally related polypeptides. We studied the effect of the multifunctional neuropoietic cytokines, including oncostatin M (OSM), leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), on anaplastic glioma cell lines. Growth and morphology of the glioma cell lines were affected differently. While IL-6 and LIF exerted no or only small minor morphological changes and growth retardation, OSM induced a marked change in morphology and a strong suppression of growth. OSM treated cells were characterized by enlargement and the formation of multiple, thin processes thus resembling mature cultured astrocytes. The growth inhibitory effects were dose dependent with a maximum exerted by addition of 50 ng/ml OSM. The inhibition of DNA synthesis by OSM could be abolished by antibodies blocking either the activity of OSM or the OSM-receptor component, gp130.
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PMID:Inhibition of growth and induction of differentiation of glioma cell lines by oncostatin M (OSM). 950 69

Cytokines regulate the expression of other cytokines in the centrally derived rat C6 glioma cell line. However, the modulation of tumor necrosis factor-alpha (TNF-alpha, a pivotal proinflammatory cytokine) in C6 cells is unknown. Here we investigated the expression of TNF-alpha mRNA in C6 glioma cells in response to TNF-alpha, interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and interferon-alpha (IFN-alpha). The data show that (1) IL-1beta induced a significant upregulation of TNF-alpha mRNA; (2) the effect of IL-1beta on TNF-alpha mRNA expression was completely blocked by the concomitant application of IL-1Ra, which suggests specificity of IL-1beta action through the IL-1 signaling receptor; (3) no detectable modulation of TNF-alpha mRNA expression was observed with the individual applications of TNF-alpha, IL-6, or IFN-alpha; (4) the concomitant treatments of TNF-alpha + IL-1beta or TNF-alpha + IL-1beta + IL-6 strongly upregulated TNF-alpha mRNA expression, whereas the concomitant application of TNF-alpha + IL-6 or IL-1beta + IL-6 induced a moderate increase; and (5) IFN-alpha significantly attenuated induction of TNF-alpha mRNA by TNF-alpha + IL-1beta + IL-6. Thus, IL-1beta, TNF-alpha and IL-6 interact to upregulate TNF-alpha mRNA expression synergistically, and IFN-alpha acts as an inhibitory cytokine in C6 glioma cells. These findings also suggest that the rat C6 glioma cell line may be used as an in vitro model to characterize cytokine-cytokine interactions.
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PMID:Modulation of TNF-alpha mRNA production in rat C6 glioma cells by TNF-alpha, IL-1beta, IL-6, and IFN-alpha: in vitro analysis of cytokine-cytokine interactions. 986 55

Interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are proinflammatory cytokines that affect the secretion of several neuroendocrine hormones. In addition, glial cells synthesize and release IL-6, suggesting a paracrine role for this cytokine in the brain. We have examined the regulation of IL-6 release from glial cells by cytokines and catecholamines. Forty ng/ml IL-1beta induced a maximal 30-fold stimulation of IL-6 release (P < 0.01); higher and lower concentrations of IL-1beta were less effective. In the presence of (Bu)2cAMP, IL-1beta induced a strongly synergistic response with respect to IL-6 release; thus, the combination of these two agents resulted in a release of IL-6 that was much larger that the release attributed to either agent alone (i.e. 30-fold higher). Similarly, the combination of IL-1beta and the diterpene forskolin (but not the inactive analog 1,9-dideoxyforskolin) or cholera toxin also resulted in a synergistic stimulation of C6 glioma IL-6 release. Thus, increases in intracellular cAMP concentrations act in a synergistic fashion with the IL-1beta signaling pathway for IL-6 release. Because catecholamines increase intracellular cAMP levels, we investigated the effects of dopamine, epinephrine, and norepinephrine on IL-6 release. The combination of 1.0 to 100 microM of each catecholamine with IL-1beta resulted in the synergistic stimulation of IL-6 release. The coincubation of the beta-agonist isoproterenol and IL-1beta resulted in a striking 25-fold synergistic induction of IL-6 release. The synergistic increases in IL-6 release caused by IL-1beta and isoproterenol as well as IL-1beta and norepinephrine were blocked by the pretreatment of C6 cells with the beta-receptor antagonist propranolol. Because lysophosphatidylcholine (LPC) may function as a second messenger for IL-1beta, we also investigated the effects of LPC. Exogenous LPC (5 to 40 microM) stimulated IL-6 release from C6 glioma cells in a concentration-related manner (P < 0.01). The coincubation of LPC with norepinephrine provoked a synergistic release in IL-6 comparable with that obtained with IL-1beta and norepinephrine. Exposure of [3H]choline-labeled C6 cells to IL-1beta resulted in an increase in the [3H]LPC species as well as a decrease in [3H]phosphatidylcholine. Finally, while TNF alpha was less efficacious than IL-1beta for the stimulation of IL-6 release from C6 cells, the combination of IL-1beta and TNF alpha resulted in a significant synergistic induction of IL-6 release. We have demonstrated that IL-1beta stimulates IL-6 release from rat C6 glioma cells via a noncAMP-mediated mechanism that may involve LPC. The synergistic induction by cytokines and catecholamines of glial cell-derived IL-6 may subsequently affect inflammatory, neurodegenerative or neurotropic processes in the CNS.
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PMID:Interleukin-1beta and catecholamines synergistically stimulate interleukin-6 release from rat C6 glioma cells in vitro: a potential role for lysophosphatidylcholine. 992 20

In this study we examine the activation of the latent Stat family of transcription factors by the gp130 family of cytokines in cell lines derived from human brain tumours. Of the cytokines tested, oncostatin M resulted in the most dramatic induction of Stat1 and Stat3 in all cell lines analysed, as assessed by the formation of protein/DNA complexes. Interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor also induced Stat complexes more selectively and to a lesser magnitude than oncostatin M. The kinetics of Stat1 and Stat3 activation was rapid and transient; the nuclear accumulation of DNA binding-proficient Stat protein was detected in the nucleus within minutes of cytokine induction. The transcriptional potential of the oncostatin M-activated Stat molecules was demonstrated in two glioma cell lines (U87-MG, SNB-19) by transient transfection experiments using a Stat-responsive reporter plasmid. Oncostatin M-dependent transcription from this reporter plasmid was reduced to uninduced levels by the inclusion of a dominant-negative Stat3 molecule, demonstrating that Stat molecules were responsible for the induction. These studies demonstrate that oncostatin M is the most potent activator of Stat molecules in a variety of brain tumour-derived cell lines, an observation that could have implications affecting the balance between proliferation/apoptosis of these cells.
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PMID:Activation of stat3 and stat1 DNA binding and transcriptional activity in human brain tumour cell lines by gp130 cytokines. 1070 21

Lead is an important neurobehavioral toxicant and may interfere with developmental processes in the brain resulting in impairment of its functions. U-373MG, a human glioma cell line, was cultured in Dulbecco's modified Eagles' medium supplemented with either 20 or 10% FBS (fetal bovine serum) to explore the possible indications for lead-induced toxicity. Although lead did not affect cell growth rate in concentrations ranging from 0.01 to 10 microM, it substantially altered gene expression analyzed by reverse-transcription polymerase chain reaction. With 10% FBS culture, lead affected the gene expression in a dose-dependent relationship. It enhanced the expression of tumor necrosis factor-alpha (TNF-alpha), but decreased those of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), gamma-aminobutyric acid (GABA) transaminase, and glutamine synthetase. With 20% FBS culture, lead also profoundly increased TNF-alpha and IL-1beta; however, it did not extensively affect the other genes examined above. Thus, the highly sensitive changes of gene expression of these cytokines or metabolic enzymes after treatments with lead acetate evidenced their usefulness as indicators for in vitro measurement of lead-induced neurotoxicity.
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PMID:In vitro aberrant gene expression as the indicator of lead-induced neurotoxicity in U-373MG cells. 1083 33

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