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)

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

Exogenously administered tumor necrosis factor-alpha (TNF-alpha) elicits several symptoms of generalized infections such as fever, increased sleep, and anorexia. The aim of the present work was to localize these effects of TNF-alpha to specific amino acid sequences of the parent molecule by characterizing the in vivo and in vitro activities of several synthetic TNF-alpha fragments. Intracerebroventricular injection of TNF-alpha elicited dose-dependent fevers and increases in non-rapid-eye-movement sleep (NREMS) in rabbits. Four fragments also promoted NREMS and five elicited monophasic fevers. All of the somnogenic fragments share the amino acid sequence 31-36. In rats, TNF-alpha and one of the fragments [TNF-alpha-(69-100)] suppressed 12-h food intake. Furthermore, TNF-alpha increased the expression of the intercellular adhesion molecule-1 and enhanced interferon-gamma-induced HLA-DR expression in human glioblastoma cell line. In contrast, none of the fragments possessed these in vitro activities. Our in vivo results support the concept that there are biologically active regions in the TNF-alpha molecule.
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PMID:Somnogenic, pyrogenic, and anorectic activities of tumor necrosis factor-alpha and TNF-alpha fragments. 135 84

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

The human U373 glioblastoma/astrocytoma cell line was found to constitutively produce and secrete a plasminogen activator and a plasminogen activator inhibitor. The plasminogen activator was identified as urokinase based on apparent molecular weight, immunoblotting with anti-urokinase antibodies, and Northern blotting with a human urokinase cDNA probe. The inhibitor secreted by U373 cells was found to be related to the PAI-1 molecule based on reactivity with anti-human PAI-1 antibodies, apparent molecular weight, and Northern blot analysis with a human PAI-1 cDNA probe. The expression of both urokinase and the PAI-1-like molecule by U373 cells could be modulated by phorbol myristate acetate or by inflammatory mediators such as interferon-gamma and interleukin-1. In the case of interleukin-1, the alpha form exhibited no detectable effect while the beta form not only elevated inhibitor levels, it also appeared to induce the production of tissue plasminogen activator. Thus, in these cells interleukin-1 beta induces alterations in PA and PAI expression and interleukin-1 alpha does not, even though the two forms are reported to utilize the same cellular receptor.
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PMID:Modulation of plasminogen activator and plasminogen activator inhibitor expression in the human U373 glioblastoma/astrocytoma cell line by inflammatory mediators. 172 61

Intercellular adhesion molecule-1 (ICAM-1) has recently been identified as one of the ligands for lymphocyte function-associated antigen-1 (LFA-1). Immunohistochemical staining of frozen tissue sections using the ICAM-1 antibody RR1/1 demonstrated significant levels of ICAM-1 expression on human glioblastoma cells and on intratumoural vascular endothelial cells. ICAM-1 was weakly expressed or absent from low grade gliomas and absent from normal and fetal brain. ICAM-1 expression was similar to that of MHC class II. HLA-DR antigens. Glioblastoma cell lines constitutively expressed ICAM-1 to a minimal or moderate extent. Surface antigen expression of ICAM-1 and ICAM-1-specific mRNA could be significantly increased by incubating glioblastoma cells with interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). IL-2, IL-4, IL-6 and transforming growth factor beta 2 (TGF-beta 2) had no significant effect on surface antigen expression. Significant enhancement of ICAM-1 expression was obtained using TNF-alpha and IL-1 beta at 1-10 U/ml and at 500 U/ml of IFN-gamma. Induction of ICAM-1 specific mRNA was observed 4 h after cytokine treatment and decreased by 24 h. Surface antigen expression of ICAM-1 increased for up to 48 h after treatment.
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PMID:Cytokine regulation of intercellular adhesion molecule-1 (ICAM-1) expression on human glioblastoma cells. 197 76

Interferon-gamma-induced tryptophan metabolism of human macrophages was compared to ten human neoplastic cell lines of various tissue origin and to normal dermal human fibroblasts. Tryptophan and metabolites were determined in supernatants of cultures, after incubation for 48 h, by high-performance liquid chromatography with ultraviolet and fluorescence detection. With the exception of two cell lines (Hep G 2, hepatoma and CaCo 2, colon adenocarcinoma) in all of the ten other cells and cell lines tryptophan degradation was induced by interferon-gamma. Five of these ten formed only kynurenine (SK-N-SH, neuroblastoma; T 24, J 82, bladder carcinoma; A 431, epidermoid carcinoma; normal dermal fibroblasts), three formed kynurenine and anthranilic acid (U 138 MG, glioblastoma; SK-HEP-1, hepatoma; A 549, lung carcinoma). Only one line, A 498 (kidney carcinoma) showed the same pattern of metabolites as macrophages (kynurenine, anthranilic acid and 3-hydroxyanthranilic acid). Interferon-gamma regulated only the activity of indoleamine 2,3-dioxygenase. All other enzyme activities detected were independent of interferon-gamma, as shown by the capacity of the cells to metabolize L-kynurenine or N-formyl-L-kynurenine. Increasing the extracellular L-tryptophan concentration resulted in a marked induction of tryptophan degradation by macrophages. Contrarily, a significant decrease of the tryptophan degrading activity was observed when the extracellular L-tryptophan concentration was increased 2-fold with SK-N-SH, T 24 and J 82, 4-fold with A 431 and A 549 and 10-fold with U 138 MG and SK-HEP-1. The activity was unaffected by extracellular L-tryptophan with dermal fibroblasts and A 498. Though interferon-gamma was the most potent inducer of tryptophan metabolism, interferon-alpha and/or -beta showed small but distinct action on some of the cells. In all cells which reacted to interferon-gamma by enhanced expression of class I and/or class II major histocompatibility complex antigens tryptophan degradation was also inducible. These results demonstrate that induction of indoleamine 2,3-dioxygenase is a common feature of interferon-gamma action, that the extent of this induction is influenced by extracellular L-tryptophan concentrations and that indoleamine 2,3-dioxygenase is the only enzyme in the formation of 3-hydroxyanthranilic acid from tryptophan which is regulated by interferon-gamma.
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PMID:Characteristics of interferon induced tryptophan metabolism in human cells in vitro. 250 Sep 76

In this report, we determined that induction of the DR alpha-chain by recombinant human interferon-gamma (IFN-gamma) in a human glioblastoma multiform cell line is transcriptionally regulated and showed that protein synthesis is not necessary for this to occur. The regions of the DR alpha-chain gene that are responsible for basal and recombinant IFN-gamma-induced gene transcription have been determined by gene transfer of a series of 5' deletion mutants in which the upstream region of the DR alpha chain was linked to a reporter gene, chloramphenicol acetyltransferase. Chloramphenicol acetyltransferase transcript and protein levels were determined by S1 nuclease protection and chloramphenicol acetyltransferase enzyme assays, respectively. By using these deletion mutants, we were able to draw the following conclusions. (i) One hundred and nine base pairs of upstream sequence contains the basic DR alpha-chain gene promoter and represents the minimal amount of sequence necessary for basal gene expression. (ii) An additional 9 base pairs of upstream sequence can mediate recombinant IFN-gamma induction. (iii) Maximal recombinant IFN-gamma induction requires at most an additional 23 base pairs of upstream sequence. (iv) The sequence between positions -267 and -141 does not appear to contain any additional positive or negative regulatory elements. These results suggest that the region between positions -141 and -109 contains a critical IFN-gamma-responsive element. Substitution mutagenesis was performed to confirm this suggestion.
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PMID:Detailed delineation of an interferon-gamma-responsive element important in human HLA-DRA gene expression in a glioblastoma multiform line. 284 68

As an in vitro model for human cerebral toxoplasmosis, we analysed the interaction between glioblastoma cells, Toxoplasma and Toxoplasma antigen-specific T-helper cells. We established 46 different human CD4+ T-cell clones from four different donors. All T-cell clones responded to Toxoplasma antigen derived from three different Toxoplasma strains. We found that the supernatants of 44 clones induced toxoplasmostasis in glioblastoma cells. The anti-parasitic effector mechanism activated in glioblastoma cells by T-cell supernatants was the induction of the tryptophan-degrading enzyme indolamine 2,3-dioxygenase. Enzyme induction, as well as the anti-parasitic effect, was blocked by a monoclonal antibody directed against interferon-gamma (IFN-gamma), and the addition of L-tryptophan to the cultures completely blocked the anti-parasitic effect induced by T-cell supernatants. The supernatants from two of the 46 established T-cell clones (3A22 and 1A15) were unable to induce indolamine 2,3-dioxygenase activity or, as expected, toxoplasmostasis in glioblastoma cells. We further analysed the supernatants from these two clones, and found that they contained large amounts of IL-4 and no, or only limited amounts of, IFN-gamma. We therefore conclude that Toxoplasma-antigen is able to activate T-helper type 1 (Th1)- and Th2-like human T cells, and only IFN-gamma-producing cells are capable of inducing anti-parasitic effector mechanisms.
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PMID:Establishment of T-helper type 1- and T-helper type 2-like human Toxoplasma antigen-specific T-cell clones. 759 Aug 86

The synthesis of C2 and factor B, the key components of complement system, is performed by various kinds of cells and is also up-regulated by interferon-gamma (IFN-gamma). By using human fibroblasts, human glioblastoma cell line A172 and monocytes, we investigated the signal-transduction mechanism for IFN-gamma-induced synthesis of C2 and factor B. The C2 and factor B synthesis induced by IFN-gamma in all three cell types was inhibited by a protein kinase C (PKC) inhibitor, 1-(5-isoquinolinyl-sulphonyl)-2-methylpiperazine (H-7). The depletion of PKC in these cell types after treatment with phorbol 12-myristate 13-acetate (PMA) resulted in inhibition of IFN-gamma-induced C2 production. In addition, IFN-gamma treatment elicited a decrease in cytoplasmic PKC in A172 cells, indicating that PKC is activated by IFN-gamma. These results suggest that PKC is crucial for IFN-gamma-induced C2 and factor B synthesis. Northern-blot analysis showed that the effects at H-7 were at least partly mediated by modulation of C2 and factor B mRNA abundance in A172 cells. Since treatment of fibroblasts and A172 cells with IFN-gamma had no effect on intracellular Ca2+ concentration, and since neither EGTA nor nifedipine inhibited C2 or factor B synthesis induced by IFN-gamma, we concluded that intracellular Ca2+ mobilization was not involved in the effect of IFN-gamma. In addition, genistein, herbimycin A and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulphonamide (W-7) had no inhibitory effect on IFN-gamma-mediated action in any of the three cell types, which suggests that IFN-gamma acts independently of tyrosine kinases and calmodulin-dependent protein kinases.
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PMID:Role of protein kinase C activation in synthesis of complement components C2 and factor B in interferon-gamma-stimulated human fibroblasts, glioblastoma cell line A172 and monocytes. 783 55

We investigated culture supernatants of peripheral blood mononuclear cells (MNC) derived from patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) for antiproliferative activity against the human glioblastoma cell line T98G. When T98G cells were cultured with condition medium containing culture supernatants of MNC from patients with HAM, the proliferation of T98G cells was significantly suppressed, compared with that of supernatants from HTLV-I seropositive carriers or seronegative controls. To clarify which population of MNC produced the antiproliferative humoral factor for T98G cells, we separated MNC into macrophage-depleted or B cell depleted populations, and further to both CD4+ and CD8+ T cells by using the panning method or plastic adherence. These studies demonstrated that the antiproliferative activity was mediated by a humoral factor produced by T cells, specifically CD4+ cells. This activity was blocked by a neutralizing monoclonal antibody against interferon-gamma (IFN-gamma). Moreover, IFN-gamma levels were elevated in the culture supernatants of CD4+ cells from HAM patients. Thus, the antiproliferative activity against T98G cells is mainly due to IFN-gamma derived from CD4+ cells of patients with HAM.
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PMID:Antiproliferative factor against the human glioblastoma cell line T98G identified in culture supernatants of CD4+ cells from patients with HTLV-I-associated myelopathy. 791 23


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