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

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.
 ...
PMID:Induction of pterin synthesis is not required for cytokine-stimulated tryptophan metabolism. 824 Feb 55

Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) gene and the MHC class II molecules are physically and functionally associated within class II-expressing cell types. These genes are generally co-expressed in various cell types and coordinately induced by cytokines such as interferon-gamma (IFN-gamma). Human Ii gene shares a regulatory mechanism with MHC class II genes via the X and Y cis-acting elements. Ii X and Y are required for constitutive expression in B lymphoid cell lines and for induction by IFN-gamma in a glioblastoma cell line. The Servenius element (S) contributes 5-fold transcriptional activity to class II gene HLA-DRA, and an S homologue has been implied in Ii gene regulation. Now we report that along with X and Y, the Ii S box functions in a positive manner to regulate Ii transcription in B cell lines but not in T cell lines. In addition, S,X, and Y are all necessary for induced expression of Ii in an IFN-gamma-regulated glioblastoma cell line and in primary untransformed glial cells. Transcriptional activity of Ii X and Y elements correlates with the presence of in vivo protein/DNA interactions in Ii-expressing cells. Most interestingly, in vivo interactions are induced upon IFN-gamma induction in a time-dependent fashion. Thus, the Ii promoter contains elements that coordinately regulate expression with the MHC class II genes, and these functional sites are contacted in vivo emphasizing their importance in Ii gene transcription.
 ...
PMID:Human major histocompatibility complex class II-associated invariant chain gene promoter. Functional analysis and in vivo protein/DNA interactions of constitutive and IFN-gamma-induced expression. 825 55

The purpose of the present study was to determine the effects of human recombinant transforming growth factor-beta 1 (TGF-beta 1) on the proliferation of normal cell and cancer cell lines and to evaluate the mechanism of TGF-beta-induced immunosuppression. Murine H238 fibrosarcoma and human UC-11 glioblastoma cells showed no proliferative change in the presence of TGF-beta, whereas the growth of human LS174T colon adenocarcinoma cells was significantly enhanced at the lower concentrations of TGF-beta. In contrast, Mono/Mac-6, a human monocyte cell line, human peripheral blood mononuclear (PBMN) cells, and BALB/c mouse spleen cells were significantly suppressed by 2.5 to 250 ng/ml of TGF-beta. In order to investigate the mode of action, TGF-beta and other cytokines were added 0, 1, and 2 days after initiation of the culture. Mono/Mac-6 cells showed that 2 days are needed for TGF-beta-induced suppression. Simultaneous addition of TGF-beta and tumor necrosis-alpha (TNF-alpha; 600 units/ml) to Mono/Mac-6 cells resulted in nearly complete suppression by day 3. IL-2, and to a lesser extent IL-4, was able to counteract the suppressive effects of TGF-beta on mitogen-stimulated spleen cells. However, our results indicate that IL-2 is not as effective in restoring responsiveness once T cell activation is well underway. IL-1 and interferon-gamma had no effects on TGF-beta-mediated immunosuppression. Since TGF-beta depressed normal cell growth and since IL-2 could effectively counteract the suppression, we assayed for IL-2 production. When normal spleen cells were treated with 2.5 ng of TGF-beta/ml, a 3.4-fold decrease in IL-2 production was observed. This is a potential mechanism for TGF-beta-mediated immunosuppression.
 ...
PMID:Modulation of transforming growth factor-beta 1 effects by cytokines. 840 27

As part of continuing studies to investigate the possible regulatory effects of cytokines on malignant astrocytes, we investigated the effects of interleukin-4 (IL-4) alone and in combination with tumor necrosis factor-alpha (TNF alpha) and/or interferon-gamma (IFN gamma) on the cell growth and major histocompatibility complex (MHC) antigen expression of a cloned human glioblastoma cell line (9C). The 9C cells were treated with IL-4 alone or in combination with TNF alpha and/or IFN gamma and were examined for proliferation by crystal violet assay and for Class II MHC antigen by flow cytometry. Results indicated that IL-4 alone did not affect 9C proliferation. In combination with TNF alpha or IFN gamma, however, IL-4 significantly and dose-dependently inhibited cell growth. As previous reports have shown, TNF alpha combined with IFN gamma exerted an additive growth suppressive effect on glioblastoma cells, probably by enhancing TNF receptor expression. This additive effect of TNF alpha and IFN gamma was further enhanced by IL-4. In contrast, IL-4 did not modulate expression of Class II MHC antigen on 9C cells, even in combination with IFN gamma, which predictably enhanced this antigen. These results suggest that IL-4 is capable of modulating glioblastoma growth only in the presence of other cytokines, such as TNF alpha and/or IFN gamma. Further, the effect of IL-4 on glioblastoma proliferation is selective and independent of the mechanisms involved in regulating MHC antigen expression.
 ...
PMID:Modulation of proliferation and antigen expression of a cloned human glioblastoma by interleukin-4 alone and in combination with tumor necrosis factor-alpha and/or interferon-gamma. 841 82

Accumulation of quinolinic acid and L-kynurenine occurs in the brain and/or blood following immune activation, and may derive from L-tryptophan following induction of indoleamine 2,3-dioxygenase and other kynurenine-pathway enzymes. In the present study a survey of various cell lines derived from either brain or systemic tissues showed that, while all cells examined responded to interferon-gamma by increased conversion of L-[13C6]tryptophan into L-kynurenine (human: B-lymphocytes, neuroblastoma, glioblastoma, lung, liver, kidney; rat brain: microglia, astrocytes and oligodendrocytes), only macrophage-derived cells (peripheral-blood mononuclear cells; THP-1, U-937) and certain liver cells (SKHep1) synthesized [13C6]quinolinic acid. Tumour necrosis factor-alpha enhanced the effects of interferon-gamma in THP-1 cells. Norharmane, 6-chloro-DL-tryptophan and 4-chloro-3-hydroxyanthranilate attenuated quinolinic acid formation by THP-1 cells with IC50 values of 51 microM, 58 microM and 0.11 microM respectively. Norharmane and 6-chloro-DL-tryptophan attenuated L-kynurenine formation with IC50 values of 43 microM and 51 microM respectively, whereas 4-chloro-3-hydroxyanthranilate had no effect on L-kynurenine accumulation. The reductions in L-kynurenine and quinolinic acid formation are consistent with the reports that norharmane is an inhibitor of indoleamine 2,3-dioxygenase, 6-chloro-DL-tryptophan is metabolized through the kynurenine pathway, and 4-chloro-3-hydroxyanthranilate is an inhibitor of 3-hydroxyanthranilate 3,4-dioxygenase. These results suggest that many tissues may contribute to the production of L-kynurenine following indoleamine 2,3-dioxygenase induction and immune activation. Quinolinic acid may be directly synthesized from L-tryptophan in both macrophages and certain types of liver cells, although uptake of quinolinic acid precursors from blood may contribute to quinolinic acid synthesis in cells that cannot convert L-kynurenine into quinolinic acid.
 ...
PMID:4-Chloro-3-hydroxyanthranilate, 6-chlorotryptophan and norharmane attenuate quinolinic acid formation by interferon-gamma-stimulated monocytes (THP-1 cells). 847 Oct 29

Twelve human glioblastoma/astrocytoma cell lines were tested for cellular adhesion molecule expression following cytokine induction in order to identify a cell line that would be suitable for functional cytokine bioimmunoassays. Many of the glioblastoma/astrocytoma cell lines were shown to inducibly express intercellular adhesion molecule-1 (ICAM-1, CD54) and vascular cell adhesion molecule-1 (VCAM-1) following stimulation with interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), tumour necrosis factor-beta (TNF-beta), and interferon-gamma (IFN-gamma), but not with any of the several other cytokines tested. The cell line U-138MG, a human glioblastoma-derived line, was the most sensitive one to IL-1 alpha/beta, TNF-alpha/beta and IFN-gamma for ICAM-1 expression, comparing well with proinflammatory cytokine-induced ICAM-1 expression in the endothelial cell hybrid EA-hy926 line, and was shown to be useful for the functional assay of the biological potencies of these individual cytokines. Such bioimmunoassays, which are developed by routine ELISA techniques, should provide valuable alternatives to existing bioassays for these cytokines.
 ...
PMID:Bioimmunoassays for proinflammatory cytokines involving cytokine-induced cellular adhesion molecule expression in human glioblastoma cell lines. 862 58

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.
 ...
PMID:Protamine enhances the activity of human recombinant interferon-gamma. 883 19

The effect of transforming growth factor-beta (TGF-beta) secreted by glioblastoma (T98G) cells on the secretion of interferon-gamma (IFN-gamma) by lymphokine-activated killer (LAK) cells stimulated with tumor cells was investigated in cocultures of LAK and Daudi cells supplemented with T98G culture supernatant, T98G culture supernatant preincubated with anti-TGF-beta 1 and anti-TGF-beta 2 neutralizing antibodies, anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, or natural human TGF-beta 1 or recombinant human TGF-beta 2. LAK cells were incubated with anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, and with T98G cells of which the supernatant contained both active and latent forms of TGF-beta 1 and TGF-beta 2, with or without neutralizing antibodies. Addition of the supernatant from T98G cells to LAK/Daudi culture caused inhibition of IFN-gamma secretion by LAK cells. The inhibition was abolished by pretreatment of the supernatants with anti-TGF-beta antibodies. Addition of TGF-beta 1 and TGF-beta 2 to the LAK/Daudi culture inhibited IFN-gamma secretion by LAK cells in a dose-dependent manner. Addition of anti-TGF-beta antibodies to the LAK culture resulted in increased IFN-gamma secretion. T98G cells failed to stimulate LAK cells to secrete more IFN-gamma. Addition of anti-TGF-beta antibodies to the LAK-T98G culture resulted in increased IFN-gamma secretion by LAK cells. These results suggest that most malignant glioma cells which secrete high levels of TGF-beta can inhibit IFN-gamma secretion by LAK cells even after tumor cell stimulation.
 ...
PMID:Transforming growth factor-beta inhibits interferon-gamma secretion by lymphokine-activated killer cells stimulated with tumor cells. 942 Apr 30

Heme oxygenase is a rate-limiting enzyme in heme catabolism that cleaves heme to form biliverdin, carbon monoxide, and iron. Heme oxygenase-1 is an inducible isozyme and is expressed in many types of cells and tissues. Large amounts of these heme degradation products may be noxious to the host, especially in the brain. We therefore searched for the factors that suppress the expression of heme oxygenase-1. Northern blot analysis showed that treatment with interferon-gamma and with interleukin-1beta for 24 h decreased the expression levels of heme oxygenase-1 mRNA to approximately 20 and approximately 50% of the control levels, respectively, in a human glioblastoma cell line, T98G. Treatment with a combination of these two cytokines additively decreased the expression levels of heme oxygenase-1 mRNA. Western blot analysis showed that the expression level of heme oxygenase-1 protein was also decreased by treatment with interferon-gamma, but not with interleukin-1beta. Moreover, pretreatment with interferon-gamma partially suppressed the induction of heme oxygenase-1 mRNA expression caused by either sodium nitroprusside, cadmium, or hemin. These findings raise the possibility that the expression of heme oxygenase-1 is down-regulated by interferon-gamma in the nervous system.
 ...
PMID:Suppression of heme oxygenase-1 mRNA expression by interferon-gamma in human glioblastoma cells. 1034 44

Production and secretion of endothelin-1 (ET-1) by a human glioblastoma cell line, T98G, were studied by radioimmunoassay and Northern blot analysis. Immunoreactive ET was detected in the culture medium of T98G (17.6 +/- 0.6 fmol/10(5) cells/24 h, mean +/- SEM, n = 5). Reverse-phase high-performance liquid chromatography (HPLC) of immunoreactive ET in the culture medium extract showed a single peak eluting in the position of ET-1. Northern blot analysis showed expression of ET-1 mRNA in T98G cells. Treatment with interferon-gamma decreased the expression of ET-1. Treatment with TNFalpha or interleukin-1beta (IL-1beta) increased the expression of ET-1. Furthermore, reverse transcriptase polymerase chain reaction (RT-PCR) showed expression of endothelin-A- and -B- (ET(A) and ET(B)) receptor mRNAs in T98G glioblastoma cells. These findings indicate that glioblastoma cells produce and secrete ET-1, and express ET receptor mRNAs. ET-1 secreted by glioblastoma cells may act locally on tumor cells, possibly as a growth modulator.
 ...
PMID:Expression of endothelin-1 and endothelin receptors in cultured human glioblastoma cells. 1107 29


<< Previous 1 2 3 4 Next >>