Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Cytokines regulate the expression of specific sets of proteins which mediate their biological effects. We have comprehensively delineated the regulation of the human tryptophanyl-tRNA synthetase (hWRS) by eight different cytokines (including IFNs) and poly(I).poly(C) in several cell lines. Six non-lymphoid cell lines were tested, and all of these produced human, IFN inducible hWRS (gamma 2) mRNA upon stimulation with IFN-gamma. In all these cell lines the level of gamma 2 mRNA increased 2-4 h after induction reaching a stable plateau after 8-12 h. The IFN-gamma induction of gamma 2 mRNA could be blocked by cycloheximide in human amniotic (AMA) cells, epithelial HeLa cells and HT1080 fibroblasts, but not in T98G glioblastoma cells. IFN-alpha and poly(I).poly(C) elicited small, transient gamma 2 responses in a few of the non-lymphoid cell lines, whereas none of the other six cytokines tested elicited a response. The six lymphoid cell lines tested did not show the same induction pattern. In the monocytic cells, THP-1, gamma 2 mRNA was highly induced by IFN-gamma, whereas in the B-cell line, Daudi, gamma 2 mRNA was transiently induced by IFN-alpha and poly(I).poly(C), and not by IFN-gamma. Altered mRNA turnover rate as a consequence of IFN-gamma treatment did not appear to play a significant role in the accumulation of gamma 2 transcript, since the stability essentially was the same in induced versus non-induced cells. We conclude that the hWRS gene is induced preferentially by IFN-gamma, and that the induction pattern resembles the one reported for the IFN induced enzyme, indoleamine 2,3-dioxygenase (IDO).
Cytokine 1995 Jan
PMID:Differential regulation of the human, interferon inducible tryptophanyl-tRNA synthetase by various cytokines in cell lines. 774 68

In order to elucidate the role of inflammatory cytokines in the central nervous system, we examined the production of two leukocyte chemoattractants, IL-8 and monocyte chemotactic and activating factor (MCAF) in brain tumor cell lines. The glioma cell lines tested exhibited high levels of IL-8 and MCAF mRNA expression upon stimulation with IL-1 or TNF-alpha, while none of the neuroblastoma cell lines expressed these cytokine mRNA. Both IL-8 and MCAF mRNA expression depended on the dose of IL-1 alpha and TNF-alpha and appeared very rapidly, reaching maximal levels at 3-6 hr, with substantial production of these cytokines in the culture supernatants. When various immunosuppressive drugs were tested, glucocorticoids but not other immunosuppressive drugs markedly inhibited the IL-1 or TNF-alpha-induced IL-8 and MCAF mRNA accumulation, suggesting that glucocorticoid is a potent regulator of these inflammatory cytokine production in the neural tissues. In addition, reverse transcription-polymerase chain reaction (RT-PCR) revealed the expression of IL-8 and MCAF mRNA expression in resected brain tumor tissues including glioblastoma, astrocytoma grade 2, ependymoma and medulloblastoma, indicating that these inflammatory cytokines are expressed in vivo.
Eur Cytokine Netw
PMID:Induction and regulation of IL-8 and MCAF production in human brain tumor cell lines and brain tumor tissues. 811 36

Activation of the immune system which occurs in inflammatory disease leads to parallel increases in pterin synthesis and increased production of neuroactive L-tryptophan metabolites. Several model systems were studied to determine whether pterins, which are cofactors for hydroxylation reactions, could be required in the oxidative kynurenine pathway of L-tryptophan degradation. Treatment of mice with interferon-gamma increased L-tryptophan metabolism without any corresponding change in tissue biopterin concentrations. Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of pterin synthesis. When pterin synthesis de novo was blocked, either by an inhibitor of GTP cyclohydrolase or because of a genetic deficiency of one of the enzymes of the pathway of pterin biosynthesis, cytokine-stimulated increases in tryptophan metabolism were unaffected. Furthermore, increasing intracellular tetrahydrobiopterin concentrations by treating cells with sepia-pterin also had no effect on markers of tryptophan metabolism. Therefore, both normal and cytokine-stimulated L-tryptophan metabolism appears to be completely independent of pterin biosynthesis.
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PMID:Induction of pterin synthesis is not required for cytokine-stimulated tryptophan metabolism. 824 Feb 55

Recombinant interferon-gamma (IFN-gamma) is a potent immune regulatory cytokine and is involved in the defense against several intracellular organisms, such as Chlamydia and Toxoplasma. Furthermore IFN-gamma is able to inhibit the growth of human tumor cell lines. The ability to inhibit the growth of intracellular organisms makes the therapeutic use of recombinant human IFN-gamma in certain patient groups, such as those with chronic granulomatous disease, leprosy, and HIV infection, very attractive. We have shown recently that IFN-gamma-mediated effects can be blocked by heparin and that this inhibitory effect can be abrogated by the addition of protamine. In this report, we show that the antagonistic effect of protamine on heparin-mediated inhibition of IFN-gamma activity is mainly due to the capacity of protamine to enhance IFN-gamma activity. We found that protamine enhances the capacity of IFN-gamma to inhibit the growth of different brain tumor cell lines, to induce indolamine 2, 3-dioxygenase activity, to induce toxoplasmostasis, and to induce MHC class II antigen expression in human glioblastoma cells and in human native fibroblasts. We were able to demonstrate that IFN-gamma binds to protamine, and, therefore, we assume that the effect of protamine on IFN-gamma is due to a direct interaction between the two molecules.
J Interferon Cytokine Res 1996 Jul
PMID:Protamine enhances the activity of human recombinant interferon-gamma. 883 19

We have previously demonstrated that a human glioblastoma cell line, T98G cells, produced high levels of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) when stimulated with IL-1 or tumor necrosis factor-alpha (TNF-alpha). In this study, we found that T98G cells are capable of producing large amounts of IL-8 and MCP-1 when cocultured with human peripheral blood monocytes or a monocytic cell line, U937 cells. Since it is possible that both glioblastoma cells and monocytes are capable of producing chemokines, we determined which type of cells actually produced IL-8 and MCP-1, by the fixation of one or the other cell type with 3% paraformaldehyde (PA). This procedure revealed that T98G cells were the main source and that PA-treated monocytes effectively stimulated IL-8 and MCP-1 production by T98G cells. Both IL-8 and MCP-1 gene expression and protein production by T98G cells were confirmed by northern blot as well as immunohistochemical staining methods. To analyze the molecules on human monocytes responsible for inducing IL-8 and MCP-1 by T98G cells, several antibodies (Abs) as well as IL-1 receptor antagonist (IL-1Ra) were tested. Anti-IL-1alpha Ab and IL-1Ra almost completely abolished the IL-8/MCP-1-inducing capacity of the PA-fixed monocytes, while no inhibition was obtained with anti-IL-1beta, anti-TNF-alpha or Abs against CD11b/18, L-selectin or ICAM-1, indicating that membrane-associated IL-1alpha is involved in the IL-8/MCP-1 induction, while secreted IL-1alpha plays a major role in this cell-to-cell, i.e., juxtacrine interaction in unfixed conditions.
Eur Cytokine Netw 1998 Mar
PMID:Interleukin-8 and monocyte chemotactic protein-1 production by a human glioblastoma cell line, T98G in coculture with monocytes: involvement of monocyte-derived interleukin-1alpha. 961 77

Cells of a human glioblastoma line were stably transfected with a glial fibrillary acidic protein (GFAP) promoter sequence/lacZ reporter gene. Following this modification, they produced Escherichia coli beta-galactosidase constitutively in amounts that could be measured through their conversion of an added fluorophore into a product readily estimated by fluorimetry. Human interferons (IFN) selectively and in a dose-dependent manner reduce the formation of beta-galactosidase in this system. We have used it as the basis for a novel assay that is sensitive (4-40 pg/ml), precise, completed in 30 h, and applicable to both type I and type II human IFNs. Statistical analysis showed interassay relative standard deviations ranging from 5% to 11%, and most individual assays revealed potencies with limits of error within 85%-115%. Neither partially trypsin-digested IFN nor the other cytokines and mitogens we tested reacted in this system, except for tumor necrosis factor-alpha (TNF-alpha). The high selectivity was further shown by the loss of response to IFN in the presence of the appropriate specific anti-IFN or anti-IFN-gamma receptor antibodies.
J Interferon Cytokine Res 1998 Jul
PMID:The beta-gal interferon assay: a new, precise and sensitive method. 971 60

Coculture of T98G glioblastoma cells with the myeloid and monocytic cell lines, HL-60, and THP-1 produced minimal amounts of interleukin-8 (IL-8). Pretreatment of HL-60 or THP-1 cells with phorbol myristate acetate (PMA) enhanced their capacity to induce IL-8 production by T98G cells. In contrast, the murine macrophage cell lines J774 A.1 and RAW 264.7 induced high levels of IL-8 production by T98G cells without PMA activation. To determine the molecules responsible for the induction of IL-8 by T98G cells, we carried out coculture experiments with a membrane fraction prepared from RAW cells and indicated that membrane-associated and free forms of murine IL-1alpha acted on human T98G cells to produce IL-8. RAW cells were unique in that increasing the number of RAW cells relative to the number of T98G cells (RAW/T98G ratio > 4:1) significantly suppressed IL-8 production by T98G cells. Because RAW cells produce large amounts of nitric oxide (NO), we assumed that the suppression of IL-8 production was ascribable to the NO produced by the RAW cells. This was supported by the inverse relationship between increasing concentrations of NO and IL-8 production seen in this coculture system. The involvement of NO in the suppression of IL-8 production was confirmed by the finding that N-monomethyl-L-arginine (NMMA), which inhibits NO production, reversed this suppression, whereas S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a strong NO generator, suppressed IL-8 production. Our results indicate that high levels of NO suppress IL-8 production by T98G cells, and murine IL-1alpha plays a major role in the induction of IL-8 production by T98G cells. It is, therefore, possible that excessive production of NO during the interaction of glioma cells with macrophages may play a regulatory role in chemokine production, thus mitigating inflammatory responses.
J Interferon Cytokine Res 1998 Oct
PMID:Nitric oxide-mediated modulation of interleukin-8 production by a human glioblastoma cell line, T98G, cocultured with myeloid and monocytic cell lines. 980 27

Glioblastoma multiforme is one of the most aggressive and frequently occurring forms of brain cancer. It originates from astrocytes and is characterized by a loss of cell cycle control frequently involving mutations in tumor suppressor genes, such as p53 and p16. Nucleoside analogs, such as acyclovir (ACV), are currently being used in the treatment of viral diseases, such as those caused by members of the herpes family. Further, ACV in combination with type I interferons (IFN) has been shown to be more effective at lower doses in treatment of viral diseases. We show here that ACV at high concentrations (up to 500 microg/ml) inhibited growth in tissue culture of the human glioblastoma cell lines T98G, SNB-19, and U-373 by as much as 68.3% while inhibiting normal human astrocytes by only 38.3%. Related to this, the tumor cells were more than sevenfold more efficient in phosphorylation of ACV to the active phosphate form than normal human astrocytes. Analogous to treatment of virus-infected cells, suboptimal concentrations of ACV were as effective as high concentrations when used in conjunction with low concentrations of IFN-gamma in inhibition of tumor cell growth. At the cellular level, ACV and IFN-gamma inhibited the cell cycle in both the G1 and S phases. The cooperative effect of ACV and IFN-gamma against the glioblastomas appears to be due to direct inhibition of DNA synthesis by ACV in the S phase of the cell cycle and induction by IFN-gamma of the tumor suppressor gene p21wAF1/CIP1, which in turn acts at the level of proliferating cell nuclear antigen (PCNA) and cyclin E/cyclin-dependent kinase 2 (Cdk2) binding and inhibition of function. These studies show that the combination of IFN-gamma and ACV at suboptimal concentrations elicits significant antiproliferative effects on the glioblastoma cell lines T98G, SNB-19, and U-373 while having very little effect on normal human astrocyte cell proliferation.
J Interferon Cytokine Res 2000 May
PMID:Inhibitory effects of IFN-gamma and acyclovir on the glioblastoma cell cycle. 1084 Oct 74

Gp130-like receptor (GPL) is a newly identified cytokine receptor. A recent study reported the involvement of GPL, together with OSMR, in the formation of the receptor complex for IL-31, a novel immune cytokine with a skin tropism. In the present work, we analyzed the signaling properties of IL-31 in glioblastoma and melanoma tumor cells. We demonstrate that in response to IL-31, its receptor complex recruits Jak1, Jak2, STAT1, -3, -5 signaling pathways, as well as the Pi3 kinase / AKT cascade. SHP-2 and Shc adapter molecules are also recruited and contribute to an increased activation of the MAP kinase pathway in response to IL-31. Different responses were observed depending on the expression of short or long GPL receptor isoform within the studied cell lines. We show that the short form of GPL receptor exerts a profound inhibitory effect on the signaling of IL-31 and behaves as a dominant negative receptor.
Eur Cytokine Netw
PMID:Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. 1562 37


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