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

In order to determine the in vivo immune response in glioblastoma, monoclonal and polyclonal antibodies specific for inflammatory leukocytes and immunoregulatory products were utilized to stain tissue from four surgical specimens. The more activated the inflammatory cells, the more activated the tumors appeared to be. In the tumor with the largest infiltration (Case 3), inflammatory cells were stained for interferon-gamma, interleukin-2, interleukin-1 beta, lymphotoxin, tumor necrosis factor-alpha, and transforming growth factor-beta. The tumor cells also expressed interleukin-1 beta, interleukin-6, transforming growth factor-beta, tumor necrosis factor-alpha, and prostaglandin E. In contrast, in the tumor with the least inflammatory response (Case 1), the tumor cells did not express any cytokines. Expression of cytokines by glioma cells was modest in the two cases with modest inflammatory responses. Cellular inflammation, primarily consisting of T cells and macrophages with few or no B cells or natural killer cells, was two- to 15-fold greater outside the tumor than within. In contrast to leukocytes outside the tumor, which were activated and expressing class II major histocompatibility antigens, leukocytes within the tumor parenchyma or at the tumor's edge were negative for these antigens. In the four specimens studied here, the tumor cells themselves were also negative for class II major histocompatibility antigens. These findings, although preliminary, suggest that inflammatory cells within gliomas are inactivated and that glioma cells may increase the expression of immunosuppressive cytokines in response to an increased lymphocyte infiltrate. This observation, if corroborated by more extensive studies, may help to explain the failure of immune treatments in glioblastoma multiforme.
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PMID:Inflammatory leukocytes associated with increased immunosuppression by glioblastoma. 131 61

This study investigated the secretion of a tumor necrosis factor (TNF) and lymphotoxin (LT) from lymphokine-activated killer (LAK) cells during co-culture with glioblastoma cell lines, autologous glioma cells, and other non-gliomatous tumor cell lines (K562 and Daudi). Cytokine secretion from peripheral blood mononuclear cells (PBMC) was also examined. The TNF activity of culture supernatants was measured by L cell cytotoxic assay, and a neutralization test using anti-TNF and/or anti-LT antibodies determined whether the cytotoxic activity was due to TNF or LT. The results show that LAK cells secrete both TNF and LT during monoculture and release increased amounts of TNF and LT with non-gliomatous tumor cell stimulation, but PBMC secrete only TNF with tumor cell stimulation. Glioblastoma or anaplastic astrocytoma cells, however, did not stimulate cytokine secretion from either LAK cells or PBMC. This indicates a discrepancy between the capability of LAK cells to lyse malignant glioma cells and cytokine secretion from LAK cells, and suggests that malignant glioma cells may produce some factors which inhibit cytokine secretion from LAK cells.
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PMID:Analysis of tumor necrosis factor and lymphotoxin secreted by incubation of lymphokine-activated killer cells with tumor cells. 137 61

Antiproliferative cytokine secretion by lymphokine-activated killer (LAK) cells during coculture with glioblastoma cell lines, autologous glioma cells, and nongliomatous tumor cell lines (Daudi and K562 cells) was assessed, as was the antiproliferative activity of the culture supernatants against the T98G (glioblastoma) cell line. A neutralization test using agents against interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), and lymphotoxin (LT) showed that antiproliferative activity was due to IFN-gamma, but not to TNF or LT. Nongliomatous tumor cells stimulated LAK cells to secrete cytokines, but gliomatous tumor cells did not. It was found that there is a discrepancy between the LAK cell capability to lyse malignant glioma cells and the ability to secrete cytokines. This may be due to the factors secreted by glioblastoma cells.
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PMID:Antiproliferative cytokines secreted by lymphokine-activated killer cells stimulated with tumor cells. 150 88

Expression of the Cytokine genes in human astroglial cell lineage was studied. Primers for 5 different human cytokine, TNF-alpha, -beta, IFN-gamma, G-CSF and GM-CSF, were used to analyze messenger RNA transcripts in 5 cultured human astrocytoma, one neuroblastoma cell lines and fresh brain specimens by polymerase chain reaction (PCR). Three out of 5 unstimulated astrocytomas, U138, U251, U373 MG and IMR32 neuroblastoma cells expressed TNF-alpha genes. After stimulation with IL-1 beta (1000 U/ml) all these cell lines expressed TNF-alpha genes. TNF-beta genes could not be detected in these cell lines even in the presence of any cytokine stimuli. We were able to detect expression of IFN-gamma genes within 2 astrocytoma cell lines (U87MG and A172), which interestingly did not show TNF-alpha activity. Constitutive expression of mRNA transcripts of GM -CSF could be detected in all astrocytoma and two out of 5 unstimulated astrocytomas, U87MG and U138MG, expressed G-CSF genes. After stimulation with IL-1 beta, all cell lines expressed G-CSF. In addition, we also examined gene expression of these cytokines within 4 human malignant astrocytoma specimens, 2 peritumoral brain and 2 autopsied normal brains. The results show that tumor and surrounding lesions express TNF-alpha (4 of 6), TNF-beta (1/6), IFN-gamma (4/6), G-CSF (3/6) and GM-CSF (5/6) but not normal brains. One tumor specimen also expresses TNF-beta as well as TNF-alpha genes (case 2). From these results, it is suspected that astroglial cell-derived cytokines may participate in local immune reactions accompanying glioma in the brain.
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PMID:[Expression of cytokine genes within astrocytoma cell lines and brain specimens]. 179 21

We examined the antitumor effect of recombinant human lymphotoxin (rHuLT) on a xenotransplantable human malignant glioma line. Tumor-bearing nude mice were treated with rHuLT for three weeks following four schedules: intratumoral injection of rHuLT 20,000 units once a week, twice a week, intravenous injection once a week and twice a week. The inhibition rate of tumor growth was 98.8%, 99.1%, 92.1% and 98.8%, respectively. Histologically, necrotic lesions were observed in the tumors of all treated mice. Thrombo-obstructive changes of tumor vessels were also seen in the tumors of mice after intravenous injection of rHuLT. None of the mice died as a result of this treatment in spite of significant body weight loss. These results indicate that rHuLT has a strong antitumor effect on a xenotransplantable human malignant glioma line.
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PMID:Antitumor effect of recombinant human lymphotoxin on a tumor line of human malignant glioma. 258 52

Growth of cultured human glioblastoma cells was profoundly inhibited by concentrated lymphokines prepared from mitogen-activated blood mononuclear cells of normal donors. Cloning efficiency of glioma cells and their absolute number were decreased as well. Partially purified leukoregulin, free of lymphotoxin, tumor necrosis factor and gamma-interferon, similarly suppressed DNA synthesis and clonogenicity. The decrease in absolute numbers of tumor target cells indicated that leukoregulin was directly cytolytic as well as cytostatic for human glioblastoma cells. Our data indicate that leukoregulin is at least one of the factors produced by activated lymphocytes which inhibits the proliferation of human glioblastoma in vitro.
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PMID:Leukoregulin inhibits the growth of human glioblastoma in vitro. 376 Jan 59

Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma.
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PMID:Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. 752 90

Human T lymphotropic virus type I (HTLV-I) is linked to adult T cell leukemia as well as to HTLV-I-associated myelopathy/tropical spastic paraparesis. In this report, we studied the effects of HTLV-I-infected cell supernatants on HUVEC, fibroblasts, and glioma cells. The HTLV-I-infected cell supernatants (HUT102 and MT-2) strongly inhibited the proliferation of HUVEC, although they enhanced the proliferation of the fibroblasts. Regarding the glioma cells, only the MT-2 supernatant showed weak inhibitory effects on the proliferation. However, the HTLV-I-uninfected cell supernatants showed no effects on these target cells. The biologic activities of both HUT102 and MT-2 supernatants were found to be dose dependent and were reduced by heat treatment at 100 degrees C for 5 min, but not at 56 degrees C for 30 min. These activities were not dependent on the concentrations of HTLV-I viral particles and were only minimally affected by the presence of anti-HTLV-I Abs. A bioassay of various cytokines revealed that the activity of TNF was much higher in the HUT102 and MT-2 supernatants than in the HTLV-I-uninfected cell supernatants (MOLT-4, Jurkat, and K-562). rTNF-alpha and rTNF-beta also showed strong inhibitory effects on HUVEC as well as on the enhancement of the fibroblast growth. With the use of Sephadex G-100 column chromatography, we obtained the highest activities from the 60- through 70-kDa fractions of the HUT102 supernatant and some activities from the 20- through 30-kDa fractions. The biologic activities of both the whole HUT102 supernatant and its active fractions were completely blocked by anti-TNF-beta mAb, although they were not blocked by anti-TNF-alpha mAb. In a Western blot assay, the 25- and 27-kDa bands of TNF-beta were shown clearly in the HUT102 supernatant, although no TNF-alpha bands appeared. These findings suggest that TNF-beta is present in either its oligomeric or monomeric form in the HTLV-I-infected cell supernatants and is also mainly responsible for the supernatants' effects on HUVECs and fibroblasts.
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PMID:TNF-beta produced by human T lymphotropic virus type I-infected cells influences the proliferation of human endothelial cells and fibroblasts. 820 18

The growth of C6 glioma cells was stimulated by TNF-alpha, IFN-gamma and IL-6 but not by TNF-beta. However, TNF-alpha and IFN-gamma but not IL-6 induced the synthesis of NO in C6 cells. Moreover, N-monomethyl-L-arginine a competitive inhibitor of NO synthase blocked TNF-alpha and IFN-gamma-dependent proliferation and NO induction on C6 cells, but had no effect on IL-6-dependent proliferation. In addition, C6 proliferation induced by TNF-alpha and IFN-gamma was specifically blocked by inhibitors of cyclic nucleotide dependent protein kinases such us H-9. Those results suggest that TNF-alpha and IFN-gamma but not IL-6 induce the growth of glia cells through the generation of NO which in turns activate a cyclic nucleotide dependent kinase.
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PMID:Involvement of nitric oxide on the cytokine induced growth of glial cell. 833 47

The transcriptional initiation and regulation of the rat serotonin 5-HT1A receptor gene were characterized. By three types of analyses, a single brain-specific site of transcriptional initiation was localized to -967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line. This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element, suggesting TATA-driven transcription of the rat 5-HT1A receptor. To identify the promoter activity of the receptor gene, progressive 5' deletions of the -2,719/-117-bp fragment of the 5-HT1A promoter linked to luciferase gene were transfected into 5-HT1A-negative (pituitary GH4C1, L6 myoblast, and C6 glioma) and 5-HT1A-positive (septal SN-48 and raphe RN46A) cell lines. Enhancer regions were identified within a fragment between nucleotides -426 and -117 that selectively enhanced transcription in 5-HT1A-positive cells. A nonselective enhancer/promoter that mediated expression in all cell lines was located upstream between -1,519 and -426 bp in a DNA segment containing consensus TATA, CCAAT, SP-1, and AP-1 elements as well as a poly-GT26 dinucleotide repeat. Strong repression of transcription in all cell lines was conferred by the region upstream of -1,519 bp that contains a 152-bp DNA segment with >80% identity to RANTES, tumor necrosis factor-beta, and other immune system genes. Our results indicate that TATA-driven expression of the 5-HT1A receptor is regulated by a novel proximal tissue-specific enhancer region, a nonselective promoter, and an upstream repressor region that is distinct from previously identified neuron-specific repressors.
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PMID:TATA-driven transcriptional initiation and regulation of the rat serotonin 5-HT1A receptor gene. 1034 31


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