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)

Rat C6 glioma cells were stably transfected with a human cDNA encoding heat shock protein (HSP)70. Immunostaining revealed the presence of largely cytosolic HSP70 in C6-hsp70 cells, but not in control (vector transfected) C6-pTK cells. Induction of nitric oxide synthase (NOS-2) expression in C6-hsp70 cells, assessed by nitrite accumulation, was significantly reduced compared to control C6-pTK cells (25+/-8% of control cell induction, P < 0.005), when induced with a maximally stimulatory combination of bacterial endotoxin lipopolysaccharide (LPS) plus a mixture of three cytokines ("CM:" TNF-alpha, IL1-beta, and IFN-gamma). Immunostaining for the transcription factor NFkappaB p65 subunit revealed decreased cytokine-dependent nuclear uptake in HSP70 expressing cells compared to control cells. Activation of C6 cell NFkappaB by LPS plus CM required IkappaB degradation by the 20S proteasome, since NOS-2 expression was blocked by a selective proteasome inhibitor. In parental C6 cells, the presence of LPS plus CM caused a rapid (within 30 min) decrease in inhibitory IkappaB-alpha protein levels, and this loss was abolished by prior heat shock of the cells. In contrast, IkappaB-alpha levels in transfected cells were not modified by the expression of HSP70. These results demonstrate that constitutive HSP70 expression in glial cells can reduce NOS-2 induction, presumably due to inhibition of NFkappaB nuclear uptake. Furthermore, whereas prevention of decreases in IkappaB-alpha can account for the suppressive effects of heat shock, the results suggest that HSP70 blocks NOS-2 induction by interfering at a later step in the NFkappaB activation pathway.
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PMID:Suppression of glial nitric oxide synthase induction by heat shock: effects on proteolytic degradation of IkappaB-alpha. 970 Oct 55

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

C6-glioma cells endogenously express both 5-HT2A receptors and inducible nitric oxide synthase (iNOS). iNOS can be induced by transcriptional activation to produce nitric oxide (NO) in response to a challenge with the pro-inflammatory cytokines TNF-alpha and IFN-gamma. Experiments were conducted to determine whether 5-HT2A receptor activation could modify the production of NO in response to the inducing agents. 1 muM DOI produced a dose-dependent inhibition of the cytokine-inducted nitrite levels of 40% which was inhibited by spiperone and ritanserin. In addition, the DOI-mediated decrease was prevented by the PKC inhibitor chelerythrine (100 nM). The effectiveness of DOI was lost when added more than two hours after the addition of inducing agent, suggesting that DOI was regulating iNOS at the level of transcription rather than post-translationally. We suggest that there is a link between the serotonergic system and NO-mediated immune responses in the brain.
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PMID:Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells. 992 54

The use of monoclonal antibodies to the tumor necrosis factor (TNF) receptors, the TNF-p55 receptor (TNF-p55R) and the TNF-p75 receptor (TNF-p75R), was evaluated to reduce the effects of TNF caused by binding to TNF-p75R. Competitive binding of anti-TNF-p55R (mAbp55R) and anti-TNF-p75R monoclonal antibodies (mAbp75R) with iodine-125-labeled TNF-alpha to GL-9 glioma cells and U937 histiocytic lymphoma cells was evaluated. The effects of mAbp55R and mAbp75R on the growth suppression by TNF-alpha of GL-9 cells and TNF-alpha production in U937 cells were also examined. mAbp75R bound to U937 cells competitively with TNF-alpha and suppressed TNF-alpha production by U937, but had no effect on the growth inhibition of GL-9 human glioma cell by TNF-alpha in vitro. These findings suggest that co-administration of TNF-p75R antagonist with TNF-alpha may decrease the toxicity of TNF-alpha administration resulting in a better therapeutic result.
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PMID:In vitro inhibition of binding of tumor necrosis factor (TNF)-alpha by monoclonal antibody to TNF receptor on glioma cell and monocyte. 1006 54

Tumor necrosis factor (TNF)-alpha has been shown to exert cytotoxic or cytostatic effects on tumor cells, but susceptibility to TNF-alpha varies among different types of cells. TNF-alpha activates a transcription factor, nuclear factor-kappaB (NF-kappaB), which induces a wide variety of genes and causes pleiotrophic responses. In this study, the relationship between susceptibility to TNF-alpha and activation of NF-kappaB was investigated in six human malignant glioma cell lines. Cell proliferation analysis revealed that only one cell line, SK-MG-1, was sensitive to TNF-alpha and that the other five, including U-251MG, were resistant. Electrophoretic mobility-shift assay showed that TNF-alpha strongly activated a subtype of NF-kappaB, the p50-p65 heterodimer, in all of the resistant cell lines tested. However, this activation was weak in the sensitive cell line, SK-MG-1. Activation of NF-kappaB by TNF-alpha in the resistant cell lines resulted in a significant increase of a reporter gene expression driven by NF-kappaB site, suggesting a possibility that activation of p50-p65 confers resistance to TNF-alpha. To test this hypothesis, we established a stable cell line that expresses an inducible dominant negative NF-kappaB (p65 DN) protein in one of the TNF-alpha-resistant cell lines, U-251MG. In the established clone, induction of p65 DN protein decreased TNF-alpha-dependent increase in the DNA binding of p50-p65 heterodimer and NF-kappaB-dependent reporter gene activity. Although no growth inhibition of this clone was observed by TNF-alpha treatment, induction of p65 DN together with TNF-alpha resulted in a significant decrease in cell number. Cell cycle analysis revealed that this growth inhibition was due to the impairment of cell cycle progression. These results indicate that an active NF-kappaB complex, such as the p50-p65 heterodimer, plays a crucial role in the progression of cell cycle in malignant glioma cells. Refractoriness to TNF-alpha treatment could be prevented by inhibiting NF-kappaB activation.
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PMID:Inhibition of nuclear factor-kappaB activation confers sensitivity to tumor necrosis factor-alpha by impairment of cell cycle progression in human glioma cells. 1048 96

1 The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) or tumour necrosis factor-alpha/interleukin-1beta/IFN-gamma (TNF-alpha/IL-1beta/IFN-gamma, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated. 2 Treatment with LPS/IFN-gamma and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 microM abrogated the LPS/IFN-gamma- and mixed cytokines-mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines-induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2-10 microM) was concentration-dependent. 3 The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase-polymerase chain reaction. 4 Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor-kappaB (NF-kappaB). Results showed that nepalolide A diminished the LPS/IFN-gamma-mediated association of NF-kappaB with consensus oligonucleotide in a concentration-dependent manner. The activation of NF-kappaB by mixed cytokines was modulated both in the extent of activation and in its time-course by nepalolide A. 5 The ability of nepalolide A to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB, as measured by immunoblotting. 6 The present study demonstrates that the attenuation of NF-kappaB activation by nepalolide A was mediated by blockade of the degradation of IkappaB, leading to suppression of the expression of iNOS.
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PMID:Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. 1051 Apr 44

The influences of Escherichia coli, Streptococcus pyogenes and lipopolysaccharides (LPSs) on the expression of cytokines and apoptosis were investigated in two glioma cell lines. IL-1beta and TNF-alpha genes were modulated by bacteria in a time dependent fashion and their expression levels varied from sources of bacteria and cell lines used. E. coli and LPSs induced apoptosis in a very limited cell population as judged by cell counts, membrane alternation and DNA break in situ. The expression of fas and IL-6 genes was not affected by bacterial components. In conclusion, aberrant expression of cytokines but not apoptosis may be the major responses of the cells of glial origin upon exposure to bacteria and their components.
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PMID:Differential expression of cytokine genes and apoptosis in glioma cell lines upon exposure to bacteria and lipopolysaccharides. 1059 86

Sodium valproate (VPA) is frequently used to treat epilepsy and convulsive disorders. Several reports have indicated that anti-epileptic drugs (AED) affect the immune system, but the mechanism has not been clear. We examined whether the commonly used AEDs, diazepam (DZP), carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and VPA, can inhibit activation of the nuclear transcription factor kappa B (NF-kappaB), in human monocytic leukemia cells (THP-1) and in human glioma cells (A-172). NF-kappaB is essential to the expression of the kappa light chain of immunoglobulin and proinflammatory cytokines. Electrophoretic mobility shift assays (EMSA) of nuclear extracts demonstrated that VPA inhibits NF-kappaB activation induced by lipopolysaccharide (LPS), but the other AEDs do not. Western blot analysis revealed that this inhibition is not linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase (CAT) assay indicated that NF-kappaB-dependent reporter gene expression is suppressed in glioma cells pretreated with VPA. VPA significantly inhibited LPS-induced production of TNF-alpha and IL-6 by THP-1 cells, whereas other AEDs did not. The findings are consistent with the idea that VPA suppresses TNF-alpha and IL-6 production via inhibition of NF-kappaB activation. Our results suggest that VPA can modulate immune responses in vitro. These findings raise the possibility that such modulation might occur with clinical use of VPA.
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PMID:Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. 1070 May 73

After adoptive transfer of pre-activated lymphocytes into the operation cavity of glioma patients, tumor regression and improved survival have been reported in some patients. Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied. In this study, we attempted to avoid time-consuming pre-activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells. Eleven patients with high-grade malignant glioma received 3 injections of 2 bispecific antibody fragments (EGFR x CD3 and EGFR x CD28) together with freshly isolated autologous lymphocytes via an Ommaya reservoir. Intracavitary fluid aspirated during immunotherapy was examined for markers of T-cell activation. Increased levels of soluble IL-2 receptor and TNF-alpha were detected in the intracavitary fluid of all patients tested. Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent MRI scans and prolonged survival. Side effects were transient and consisted of fever, nausea, headache and aggravation of pre-existing neurologic deficits. These adverse effects were most likely due to the antibody construct containing anti-CD3 specificity. Two patients developed cerebral edema and required steroid treatment.
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PMID:Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes: evidence for in situ t-cell activation and therapeutic efficacy. 1114 49

The major goal of this study was to determine if treatment with the newly constructed plasmid vector for tumor necrosis factor-alpha (pGL1-TNF-alpha) could enhance the radiation-induced growth reduction of C6 rat glioma. In addition, two different forms of ionizing radiation (gamma-rays and protons) were utilized. Body and spleen mass, leukocyte blastogenesis, and flow cytometry analysis of cell populations in blood and spleen were performed to detect toxicity, if any, and to identify mechanisms that may correlate with the anti-tumor action of combination therapy. C6 tumor cells were implanted subcutaneously into athymic mice and allowed to become established before treatment initiation. pGL1-TNF-alpha was injected into the implanted tumors, which were then irradiated 16-18 hr later; each modality was administered three times over 8-9 days. The addition of pGL1-TNF-alpha significantly enhanced the anti-tumor effect of radiation (p < 0.05). The effect was more than additive, since pGL1-TNF-alpha alone did not slow tumor progression and radiation alone had only a modest effect. Administration of pGL1-TNF-alpha together with proton radiation resulted in tumor volumes that were 23% smaller than those following pGL1-TNF-alpha + gamma-ray treatment; a similar differential in tumor size was observed in the groups receiving only radiation. Body weights and blood and spleen cell analyses did not reveal treatment-related toxicity. High basal proliferation of blood leukocytes and increased B cell levels in the spleen were associated with pGL1-TNF-alpha + 60Co (gamma-radiation) or proton treatment. Overall, the results suggest that the pGL1-TNF-alpha/radiation combination is effective and safe under the conditions employed. This is the first study to combine gene and proton radiation therapy and to show, under controlled experimental conditions, that proton radiation may have a greater effect against malignant tumors compared to the same physical dose of gamma-radiation.
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PMID:Combination of pGL1-TNF-alpha gene and radiation (proton and gamma-ray) therapy against brain tumor. 1120 48


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