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)

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

Interleukin-1 (IL-1) is an antiproliferative factor for growing human melanoma A375-C6 cells. To define the molecular basis for the action of IL-1, we set out to identify early genes induced by the cytokine in the absence of de novo protein synthesis. cDNA libraries were constructed from A375-C6 cells that were exposed or unexposed to IL-1 plus cycloheximide. Subtractive hybridization was used to prepare a library that was enriched for IL-1-induced clones. Two of these clones were shown by Northern analysis to represent IL-1-inducible genes. Nucleotide sequencing identified these genes as gro/melanoma growth stimulatory activity, which encodes a cell secretory product, and c-jun, which encodes a transcription factor. IL-1 caused persistent steady state elevation of gro mRNA but only transient induction of c-jun. Northern analysis using gene probes for the transcription factors c-fos and Egr-1 revealed that IL-1 induced c-fos but not Egr-1 expression in these cells. This indicates that differential early gene expression characterizes the growth-inhibitory action of IL-1. In contrast, serum, which is mitogenic for these cells, induces c-jun, c-fos, and Egr-1, but not gro expression. These data imply that in A375-C6 cells, both growth-inhibitory and stimulatory signals can channel their action through c-fos and c-jun genes. As gro induction was specifically associated with the antimitogenic action of IL-1, we studied the effect of the cytokine on gro gene expression in other types of cells. IL-1 was mitogenic for human glioblastoma and monkey kidney epithelial cells and induced gro whereas other mitogens did not. Thus, IL-1 can induce gro gene expression in diverse cell types, whether it acts to stimulate or inhibit proliferation. Like other cytokines gro may play diverse cell-specific roles in growth control.
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PMID:Antimitogenic and mitogenic actions of interleukin-1 in diverse cell types are associated with induction of gro gene expression. 198 93

Human glioblastoma cells secrete a factor termed glioblastoma derived T cell suppressor factor (G-TsF) or transforming growth factor beta 2 (TGF-beta 2) which inhibits the response of T cells to mitogenic or antigenic stimulation. In the present study we isolated the promoter region of the G-TsF/TGF-beta 2 gene. The promoter region shares no homology to the promoter of the TGF-beta 1 or the 5' region of the TGF-beta 3 gene and harbours several familiar DNA motifs, including the cytokine-1 region, an octamer-like sequence, Sp1- and AP-2-like elements and a putative NF-kappa B site. In contrast to the TGF-beta 1 gene, the G-TsF/TGF-beta 2 gene contains three TATA-like sequences but lacks an AP-1 site. To understand the cell type specificity of expression of G-TsF/TGF-beta 2, the individual contribution of the DNA elements detected in the promoter has to be analysed in further studies.
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PMID:Sequence analysis of the promoter region of the glioblastoma derived T cell suppressor factor/transforming growth factor (TGF)-beta 2 gene reveals striking differences to the TGF-beta 1 and -beta 3 genes. 222 34

The secretion of transforming growth factor-beta (TGF-beta), a growth inhibitory factor with immunosuppressive properties, was investigated in one glioblastoma cell line and seven surgically resected malignant glioma cells. Cultured cells from surgically resected tumors were examined immunohistochemically for glial fibrillary acidic protein (GFAP) and S-100 protein. The levels of TGF-beta 1 and TGF-beta 2 in culture supernatants from malignant glioma cells were determined by a specific bioassay using anti-TGF-beta 1 and anti-TGF-beta 2 antibodies. Two glioblastoma cell lines were cultured in the presence of TGF-beta 1 or TGF-beta 2 to assess the effect of TGF-beta on the growth of glioblastoma cells. Cultured cells from surgically resected tumors were positive for both GFAP and S-100 protein. Both active and latent forms of TGF-beta 1 and TGF-beta 2 were detected in the culture supernatants from malignant gliomas, except in one patient with anaplastic astrocytoma which secreted only latent forms of TGF-beta 1 and TGF-beta 2. There was no statistical difference in the levels of TGF-beta 1 and TGF-beta 2 in glioblastomas and anaplastic astrocytomas. Neither TGF-beta 1 nor TGF-beta 2 affected the growth of glioblastoma cells. These findings suggest that most malignant glioma cells secrete both TGF-beta 1 and TGF-beta 2, can convert TGF-beta from a latent to active form, and may suppress cytokine secretion by activated lymphocytes in vivo as well as in vitro.
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PMID:Secretion of transforming growth factor-beta 1 and -beta 2 by malignant glioma cells. 747 84

Interleukin-11 (IL-11) is a pleiotropic cytokine with important effects on hematopoietic and other cells. IL-11 was originally described as a product of stromal cell lines and fibroblasts. Using RT-PCR, Northern blotting, and ELISA we demonstrated that the human U373 and U87 glioblastoma cell lines expressed IL-11 and its encoding mRNA when stimulated with IL-1 beta, phorbol ester, and calcium ionophore. The neuroblastoma cell line SH-SY5Y did not express IL-11 mRNA in response to these agents. Cerebral expression of IL-11 by glial cells is important because IL-11 has been shown to have effects on neuronal electrophysiology, has overlapping functions with the neuroactive cytokine interleukin-6, and is part of the gp130-associated neuropoietic family of cytokines.
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PMID:Expression of interleukin-11 and its encoding mRNA by glioblastoma cells. 750 Dec 71

Granulocyte-colony-stimulating factor (G-CSF) is a hematopoietic cytokine that regulates the differentiation of myeloid progenitors and the function of mature neutrophils. It is produced in vitro by monocytes/macrophages, mesothelial cells, fibroblasts and endothelial cells after appropriate induction by inflammatory mediators like IL-1 and TNF. Normal as well as tumorous glial cells can also be induced to produce CSFs in vitro. However, little is yet known about the in vivo expression of G-CSF as a mediator in inflammation and malignancy within the human central nervous system. The aim of the present study was to investigate by immunostaining the expression of the G-CSF protein within non-tumorous and tumorous glial tissues, and primitive neuroectodermal tumors. Using the murine monoclonal anti-G-CSF TM 82/60 antibody, we found high G-CSF expression in astrocytoma WHO grades I and II and reactive brain tissue, low expression in astrocytoma WHO grade III, and none in glioblastoma, oligodendroglioma WHO grades II and III, and medulloblastoma. In consecutive sections of the tissue samples, G-CSF protein was localized in GFAP-positive glial cells, but not in macrophages/microglial cells, which expressed HLA-DR, detected by the antibody CR3/43. Computer-assisted microdensitometric evaluation of the intensity of immunostaining for G-CSF and statistic analysis of the data revealed significant differences between the diagnostic entities studied (p < 0.0001). We conclude that in vivo expression of G-CSF is a characteristic of reactive as well as tumorous astrocytes, with the latter losing this feature at higher degrees of dedifferentiation.
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PMID:Immunolocalization of granulocyte-colony-stimulating factor in human glial and primitive neuroectodermal tumors. 751 14

To elucidate which cytokine receptors may be expressed by human glioblastoma and normal astrocytic cells, the presence of messenger ribonucleic acid (RNA) for a number of cytokine receptors was examined in 16 glioblastoma cell lines and adult and fetal astrocytes. A complementary deoxyribonucleic acid copy of total RNA was synthesized and amplified with specific primers using the polymerase chain reaction method. The receptors studied were interleukin (IL)-1 receptor type I (IL-1RI) and type II (IL-1RII), p75 and p55 tumor necrosis factor (TNF) receptors (p75TNFR and p55TNFR), interferon (IFN)-alpha/beta and -gamma receptors (IFN-alpha/beta R and IFN-gamma R), granulocyte-macrophage (GM) colony-stimulating factors receptor alpha subunit (GM-CSFR), G-CSF receptor (G-CSFR), M-CSF receptor (c-fms, M-CSFR), stem cell factor receptor (c-kit, SCFR), IL-6 receptor (IL-6R), and IL-8 receptor (IL-8R). Transcripts for IL-1RI, p55TNFR, IFN-alpha/beta R, and IFN-gamma R were present in all cell lines. The presence of IL-1RII, p75TNFR, GM-CSFR, M-CSFR, SCFR, IL-6R, and IL-8R was identified in 13, eight, seven, eight, 14, three, and one cell lines, respectively. Normal astrocytes were positive for IL-1RI, p75TNFR, p55TNFR, IFN-alpha/beta R, IFN-gamma R, M-CSFR, and SCFR, showing a similarity to glioblastoma cells. Expression of IL-1RII was observed in adult astrocytes but not in fetal astrocytes. Furthermore, gene expression was assessed in normal brain tissue and 11 glioblastoma tissue specimens. The normal brain tissue expressed IL-1RI, IL-1RII, IFN-alpha/beta R, M-CSFR, and SCFR. Of the 11 glioblastoma tissue specimens, IL-1RI was positive in 11, IL-1RII in 10, p75TNFR in nine, p55TNFR in nine, IFN-alpha/beta R in 10, IFN-gamma R in 10, GM-CSFR in two, G-CSFR in three, IL-8R in eight, and M-CSFR and SCFR in 11. These expressions were consistent with those in the cell lines, except for IL-8R. It is concluded that glioblastoma cells and normal astrocytes express a similar set of cytokine receptor genes in vitro and in vivo. Possible autocrine loops are suggested for IL-1 alpha/IL-1RI, TNF-alpha/p55TNFR, IFN-beta/IFN-alpha/beta R, M-CSF/M-CSFR, and SCF/SCFR in glioblastomas.
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PMID:Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction. 751 61

The infiltration of leukocytes into the central nervous system is associated with many pathologic conditions of the brain. The mechanisms by which these immune cells can penetrate the blood-brain barrier and remain within the brain are not understood. However, elevated brain levels of the pro-inflammatory cytokine IL-1 appear to accompany pathogenesis. The present study provides the first evidence that IL-1 can induce the expression of adhesion molecules for leukocytes on glial cells and suggests a role for the transcription factor NF-kappa B in the induction process. Human rIL-1 alpha was found to induce the expression of the cell adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) but not E-selectin in human 1321N1 astrocytoma. Both VCAM-1 and ICAM-1 were detectable from 3 h and remained sustained for up to 72 h. Induction was inhibited by the IL-1 receptor antagonist. IL-1 alpha was also shown to induce the expression of VCAM-1 and ICAM-1 in a receptor-dependent fashion in human A172 glioblastoma. Activation of the transcription factor NF-kappa B was also observed in 1321N1 astrocytoma in response to IL-1 alpha treatment and was similarly abolished by pretreatment of cells with antagonist. Activated NF-kappa B was apparent from 20 min and remained for up to 24 h. N-acetylcysteine (NAC) and pyrollidinedithiocarbamate (PDTC), which were shown to inhibit activation of NF-kappa B in Jurkat E6.1 lymphoblasts and EL4.NOB-1 thymoma, failed to block IL-1 activation of NF-kappa B in 1321N1 astrocytoma. However, both of these antioxidants demonstrated complex modulatory effects on the induction of cell adhesion molecule expression by IL-1. The induction of VCAM-1 but not of ICAM-1 proved susceptible to inhibition by both PDTC and NAC. The expression of adhesion molecules for leukocytes on glial cells in response to IL-1 may represent an important mechanism for retention of immune cells in the central nervous system that may be a prologue to inflammatory conditions in the brain.
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PMID:Activation of NF-kappa B and induction of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression in human glial cells by IL-1. Modulation by antioxidants. 752 69

Interleukin 10 (Il-10) was initially discovered on the basis of its ability to suppress cytokine synthesis. Additionally, it can exert immunosuppressive effects on a variety of cell types. Since patients with malignant gliomas present with a general impairment of the immune system, we sought to investigate if IL-10 is expressed in the glioma tissue. Using RT-PCR, IL-10 mRNA levels were determined in 37 glial tumors of different grades including 2 recurrencies, 3 specimens from normal brain tissue and 3 glioblastoma cell lines. Expression of IL-10 mRNA was demonstrable in all tumors as well as in normal brain. High grade tumors and recurrent cases expressed significantly higher amounts of IL-10 specific mRNA compared to low grade tumors, while 2 out of 3 cell lines showed only weak constitutive expression. We suggest, that IL-10 may contribute to the progression of astrocytomas by allowing the tumor cells to attenuate the T-cell immune response and evade immune detection.
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PMID:[Increased amounts of IL-10 mRNA in anaplastic astrocytomas and glioblastoma multiforme]. 753 12

Tumor necrosis factor-alpha is a pluripotent cytokine that is reportedly mitogenic to astrocytes. We examined expression of the astrocyte intermediate filament component glial fibrillary acidic protein in astrocyte cultures and the U373 glioblastoma cell line after treatment with tumor necrosis factor-alpha. Treatment with tumor necrosis factor-alpha for 72 h resulted in a decrease in content of glial fibrillary acidic protein and its encoding mRNA. At the same time, tumor necrosis factor-alpha treatment increased the expression of the cytokine interleukin-6 by astrocytes. The decrease in glial fibrillary acidic protein expression was greater when cells were subconfluent than when they were confluent. Thymidine uptake studies demonstrated that U373 cells proliferated in response to tumor necrosis factor-alpha, but primary neonatal astrocytes did not. However, in both U373 cells and primary astrocytes tumor necrosis factor-alpha induced an increase in total cellular protein content. Treatment of astrocytes and U373 cells for 72 h with the mitogenic cytokine basic fibroblast growth factor also induced a decrease in glial fibrillary acidic protein content and an increase in total protein level, demonstrating that this effect is not specific for tumor necrosis factor-alpha. The decrease in content of glial fibrillary acidic protein detected after tumor necrosis factor-alpha treatment is most likely due to dilution by other proteins that are synthesized rapidly in response to cytokine stimulation.
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PMID:Tumor necrosis factor-alpha and basic fibroblast growth factor decrease glial fibrillary acidic protein and its encoding mRNA in astrocyte cultures and glioblastoma cells. 759 70


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