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)

The intrathecal immune response in neoplastic meningitis (NM) was studied by quantitation of immune parameters such as immunoglobulin G (IgG); IgM; interleukins (IL) 1, 2, 4, and 6; soluble IL-2 receptors (sIL-2R); interferon gamma (IFNy); tumor necrosis factor-alpha (TNF alpha); and three tumor markers, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and fibronectin (FN), in 47 paired cerebrospinal fluid (CSF) and serum samples from patients with NM from different carcinomas, malignant melanoma, and lymphoma. Elevated IgG and IgM indices, CSF oligoclonal Ig bands, and CSF IL-6 indicated an intrathecal immune activation in most patients with NM. Results for IL-1, IL-2, and IL-4 were always negative. sIL-2R and IFNy were detected occasionally but not associated with specific malignant neoplasms. CSF TNF alpha was detected only in NM from cases of malignant melanoma. None of the immune parameters proved useful for the differentiation of NM from autoimmune or inflammatory conditions. Immune parameters were not correlated with tumor markers CEA, AFP, or FN. Results for AFP were positive only in a case of glioblastoma. CEA was a useful and specific diagnostic parameter in carcinomatous NM. CSF FN levels frequently were elevated but are not specific for NM.
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PMID:Tumor cell dissemination triggers an intrathecal immune response in neoplastic meningitis. 137 13

The pathogenetic mechanisms underlying the development of reactive arthritis and the functional capacities of synovial T cells specific for Yersinia enterocolitica are still unclear. In this study we have determined the cytokine secretion patterns of 24 CD4+ synovial fluid (SF)-derived T cell clones from 2 patients with Yersinia-induced reactive arthritis, 16 clones specific for different Yersinia antigens and 8 clones as controls. The clones specific for Yersinia antigens predominantly belong to the T helper cell 1 (Th1) subset with production of interferon (IFN)-gamma and interleukin (IL)-2, but no IL-4, whereas SF T cells not reactive with Yersinia antigens produce IL-2, IL-4 and IFN-gamma and thus belonged to the Th0 subset. Moreover, short-term T cell lines established from SF and peripheral blood showed the same pattern. To further analyze the functional relevance of these data we investigated the influence of IFN-gamma and IL-4 on the intracellular killing of Yersinia in a human glioblastoma cell line. Our data show that the Th1 cytokine IFN-gamma promotes intracellular killing of Yersinia, whereas this effect is antagonized by the Th2 cytokine IL-4. Furthermore, the Th2 cytokine IL-10 inhibited the antigen-specific proliferative response and IFN-gamma and IL-2 production by the Th1 cells. These results provide insight into the antibacterial mechanisms at work in reactive arthritis after infection with Yersinia enterocolitica and, for the first time, reveal the cross-regulatory properties of cytokines derived from Th1 and Th2 cells in a human immune response to bacterial antigens.
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PMID:Predominance of Th1-type T cells in synovial fluid of patients with Yersinia-induced reactive arthritis. 142 4

We report the expression of different interleukins (IL) in four human glioblastoma and neuroblastoma cell lines. The glioblastoma cell line LI, expresses IL-1 beta and IL-6 mRNA, though not IL-2 and IL-4. The expression of the former gene is modulated by retinoic acid. Two cell clones [BE(2)-C and BE(2)-M17] as well as the neuroblastoma cell line SK-N-BE(2), from which both clones were derived, express IL-6 mRNA, but not IL-1 beta, IL-2 or IL-4. Both IL-1 beta and IL-6 cytokines are known to increase hypothalamic CRH mRNA, a gene reported to be expressed in all these cell lines. The production of both cytokines and neuropeptides indicates a complex dialogue between tumour cells and anti-tumour immunity.
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PMID:Interleukin-1 beta and interleukin-6 mRNA are expressed in human glioblastoma and neuroblastoma cells respectively. 160 28

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

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

Glioblastoma, glioma or neuroblastoma cells were examined for the expression of IL-4 receptors (IL-4R) by flow cytometric analysis and 125I-IL-4 binding. These cancer cell lines expressed IL-4R which were of high affinity (KD = 700 x 10(-12) M) on glioblastoma cells. To investigate the function of these receptors and to target potent cytotoxic antitumor agents to human neurological cancers, we utilized IL4-PE4E, which is composed of IL-4 and mutant Pseudomonas exotoxin (IL4-PE4E). This chimeric molecule was cytotoxic toward human glioblastoma, neuroblastoma and glioma tumor cells in a dose-dependent manner. The cytotoxicity of IL4-PE4E was specific, since it was neutralized by excess IL-4, and by an anti-IL-4 monoclonal antibody in all types of brain tumor tested. IL2-PE4E and IL6-PE4E were not cytotoxic, nor was an IL4-PE4E mutant lacking ADP-ribosylating activity, indicating the IL4-PE4E-mediated cytotoxicity of the brain tumor cells required both IL-4R binding and enzymatic toxin activity. These data indicate that human neurological cancer cells express IL-4R which are targets for the cytotoxic effects of IL4-toxin. In addition, our data also suggest that IL4-PE4E should be studied further as a potential treatment for human neurological cancers.
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PMID:Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the toxic effects of IL4-Pseudomonas exotoxin chimeric protein. 805 54

Immunosuppressive events are often observed in glioblastoma-bearing patients. We tested the response of circulating lymphocytes from glioblastoma patients to low concentrations of interleukin (IL)-4 and IL-2 after lectin activation or specific in vitro stimulation by autologous tumor cells. In the presence of IL-2, IL-4 up-regulates the proliferation rate of phytohemagglutinin (PHA)-P-stimulated glioblastoma patients' peripheral blood lymphocytes (PBL)s. Allogeneically- and syngeneically-stimulated PBLs of these patients present an increased proliferation rate in the presence of IL-4. This specifically stimulated lymphocyte population presents a very low proportion of CD8+ cells. This proportion is slightly increased in the presence of IL-4. Our results indicate that the glioblastoma cell-imposed inhibition on T-cells can be partly overcome by low concentrations of IL-4 during in vitro stimulation. Our experiments also demonstrate that glioblastoma-bearing patients' PBLs constitute a good model in which to study the effects of IL-4.
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PMID:Interleukin-4 affects phenotype and proliferative response of peripheral blood lymphocytes from glioblastoma patients after specific or nonspecific in vitro stimulation. 813 43

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.
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PMID:Modulation of transforming growth factor-beta 1 effects by cytokines. 840 27

Effective treatment is lacking for malignant glioblastoma/astrocytoma. We have identified interleukin-4 receptors (IL-4R) on human malignant astrocytoma. We demonstrate that 16 of 21 surgical samples of high-grade astrocytoma and glioblastoma but not normal brain tissues expressed IL-4R as assessed by reverse transcriptase PCR. We further demonstrate that human malignant astrocytoma cell lines express high-affinity IL-4R. Using a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin A, we observed that this toxin IL4(38-37)-PE38KDEL) is highly cytotoxic to IL-4R-bearing glioblastoma cells. Compared with a previously reported IL4-PE chimeric protein (IL-PE4E), IL4(38-37)-PE38KDEL bound with higher affinity and was 3-30-fold more cytotoxic to glioblastoma cell lines. Upon intrathecal administration in monkeys, high cerebrospinal fluid IL4(38-37)-PE38KDEL levels were achieved using 2- and 6-microg/kg doses without any central nervous system or other abnormalities. IL4(38-37)-PE38KDEL levels were not detectable in the serum of any monkey studied. When IL4(38-37)-PE38KDEL was injected into the right frontal cortex of rats, localized necrosis was observed at 1000-ng/ml doses but not at < or = 100-ng/ml doses. We conclude that by localized administration, nontoxic levels of IL4(38-37)-PE38KDEL can be achieved, which may have significant cytotoxic activity against malignant astrocytoma.
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PMID:Preclinical development of a recombinant toxin containing circularly permuted interleukin 4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. 1145 21

Exposure of cells to protein tyrosine phosphatase (PTP) inhibitors causes an increase in the phosphotyrosine content of many cellular proteins. However, the level at which the primary signaling event is affected is still unclear. We show that Jaks are activated by tyrosine phosphorylation in cells that are briefly exposed to the PTP inhibitor pervanadate (PV), resulting in tyrosine phosphorylation and functional activation of Stat6 (in addition to other Stats). Mutant cell lines that lack Jak1 activity fail to support PV-mediated [or interleukin 4 (IL-4)-dependent] activation of Stat6 but can be rescued by complementation with functional Jak1. The docking sites for both Jak1 and Stat6 reside in the cytoplasmic domain of the IL-4 receptor alpha-chain (IL-4Ralpha). The glioblastoma-derived cell lines T98G, GRE, and M007, which do not express the IL-4Ralpha chain, fail to support Stat6 activation in response to either IL-4 or PV. Complementation of T98G cells with the IL-4Ralpha restores both PV-mediated and IL-4-dependent Stat6 activation. Murine L929 cells, which do not express the gamma common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation. Thus, Stat6 activation by PV is an IL-4Ralpha-mediated, Jak1-dependent event that is independent of receptor dimerization. We propose that receptor-associated constitutive PTP activity functions to down-regulate persistent, receptor-linked kinase activity. Inhibition or deletion of PTP activity results in constitutive activation of cytokine signaling pathways.
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PMID:Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1. 923 16


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