Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 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

Recent progress has been made concerning the understanding of the molecular pathways that mediate the growth suppressive effects of inhibitory cytokines. Interferons, interleukin-6 and transforming growth factor-beta were investigated in these studies. Cell lines that display growth sensitivity to all three cytokines and growth resistant derivates provided a suitable genetic background to determine whether common or unique post-receptor elements mediate the effects of each cytokine. Three nuclear genes, c-myc, RB, and cyclin A were found to be common key downstream targets along the cytokine induced growth suppressive pathways. Genetic and pharmacological manipulations proved that these molecular responses fall into few complementary pathways that function in parallel to achieve the cytokine mediated G0/G1 arrest. New strategies, such as knock out anti-sense gene cloning were developed and they currently provide powerful tools for the isolation of genes along the signaling pathways of growth arrest.
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PMID:Cytokine triggered molecular pathways that control cell cycle arrest. 138 55

Recent reports have suggested that transforming growth factor-beta (TGF-beta) may have an important role in IgA immune responses, e.g. induction of surface IgM+ B cells to commit to IgA. TGF-beta is also an important regulatory cytokine for the maturation of intestinal epithelial cells. Using the IEC-6 rat intestinal epithelial cell line as a model system, TGF-beta 1 was found to enhance interleukin-6 (IL-6) secretion by the IEC-6 cells. The IL-6 was produced in a dose-dependent manner and secretion could be specifically inhibited by an anti-TGF-beta 1 antibody. IL-6 production by the IEC-6 cells was confirmed by using a rabbit anti-mouse IL-6 antibody which completely neutralized the IL-6 present in the IEC-6 cell supernatant. The enhancement of IL-6 secretion was found to involve a low-level enhancement in the expression of RNA for IL-6. The induction of IL-6 secretion was also reversible when TGF-beta was removed. These results suggest that the action of TGF-beta on intestinal epithelial cells may play an important role in immune responses at the intestinal mucosa.
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PMID:Transforming growth factor-beta enhances interleukin-6 secretion by intestinal epithelial cells. 139 66

Stromal cells of bone marrow origin produce a variety of known cytokines and some factors exhibiting apparently new biological activities. Several of these were identified by the study of cell to cell interactions and were not found in detectable amounts in media conditioned by the cells. We describe here a culture system that enables the release of stromal cytokines into medium free of any added proteins and supplemented with peptides from casein hydrolysate (0.1%). The absence of serum proteins allows extensive concentration and monitoring of activities that are otherwise undetectable. Stromal cells of the MBA-2.1 clonal cell line were seeded in a stationary bed reactor packed with a carrier of non-woven fabric matrix. After a proliferation phase with serum containing medium, the cells were maintained for over 10 months in protein-free medium. Throughout this extended incubation in the absence of serum or serum replacing proteins, stromal cells retained their viability and continuously released transforming growth factor-beta (TGF-beta), macrophage-colony stimulating factor (M-CSF) and restrictin-P, a cytotoxic factor that specifically arrested the growth of plasmacytoma cells. In addition, interleukin-6 (IL-6) was first undetectable, and later in culture its titer reached a maximum of 180,000 international units (IU)/ml. Concomitantly, the production of restrictin-P diminished and reached its lowest levels at the end of 10 months. The results may imply a possible causal relationship between the expression of IL-6 and restrictin-P, since no similarly significant changes were observed in the titers of M-CSF and TGF-beta. This novel bioreactor system may be adaptable for efficient production of different cytokines under absolute serum-free conditions.
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PMID:Dynamic changes in cytokine secretion by stromal cells during prolonged maintenance under protein-free conditions. 145 17

Recent investigations of immunologic events in systemic sclerosis focus on the identification of which immune system cells are participating in the disease process, what antigens are stimulating the T and B cells, which cytokines are involved, and which cell adhesion molecules promote cell-cell and cell-extracellular matrix interactions. Increased numbers of gamma/delta and activated CD4+ T cells are present in involved skin of line-200 chickens, an animal model of systemic sclerosis. CD4+ T cells from patients with systemic sclerosis are stimulated by human type I collagen, and immunoglobulins from some patients with systemic sclerosis bind retroviral proteins, the terminal galactosyl (alpha 1-3)-galactose disaccharide of laminin, or a 138 amino acid region of the PM-Scl antigen. The development of an anticentromere antibody response in patients with systemic sclerosis appears to require the presence of a polar amino acid at position 26 in the antigen-binding cleft of the HLA-DQB1 molecule. Interleukin-2, interleukin-4, interleukin-6, and transforming growth factor-beta have been implicated as cytokines that may be involved in the pathogenesis of systemic sclerosis. Increased expression of intercellular adhesion molecule 1 (ICAM-1) on systemic sclerosis fibroblasts is responsible for increased binding of T cells to those fibroblasts through ICAM-1/lymphocyte function-associated antigen 1 interactions. beta 1 and beta 2 integrins, ICAM-1, and endothelial leukocyte adhesion molecule 1 all may be involved in the homing of lymphocytes to involved skin in patients with systemic sclerosis.
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PMID:Immunologic aspects of scleroderma. 145 82

Scleroderma fibrotic lesions demonstrate vascular disease, mononuclear cell infiltrates, and increased collagen. Fibroblasts in these lesions are activated to synthesize increased extracellular matrix substances, a phenotype that continues when these cells are removed and grown in tissue culture. Levels of messenger RNA for connective-tissue substances, measured directly in biopsies of scleroderma skin, show increased message for type I collagen, but not type III collagen or fibronectin. Increased procollagen type I in scleroderma skin occurs in the papillary dermis, perivascular areas, and deep interstitium, even in skin areas that are not yet fibrotic. Scleroderma fibroblasts express more intercellular adhesion molecule 1 on their surfaces than do normal cells, and this molecule is increased in endothelial cells, mononuclear cells, and fibroblasts. In vitro scleroderma fibroblasts adhere more frequently to extracellular matrix substances and retract collagen lattices to a greater extent. Peripheral blood lymphocytes from scleroderma patients produce excessive amounts of interleukin-2 when incubated with type I collagen, and circulating basophils release more histamine than do normal cells. There is evidence for activated eosinophils both in the dermis and pulmonary lesions in scleroderma, which may play a role in fibrosis. Transforming growth factor-beta is overexpressed by alveolar macrophages from patients with fibrotic pulmonary disease. Scleroderma fibroblasts, when exposed to transforming growth factor-beta, overexpress the alpha-type receptor for platelet-derived growth factor. Scleroderma sera more frequently contain measurable quantities of interleukin-4, interleukin-6, and interleukin-2. Interleukin-4 causes adult dermal fibroblasts to proliferate and to make interleukin-6. Interleukin-6 has been shown to stimulate fibroblast synthesis of collagen and glycosaminoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Connective tissue metabolism including cytokines in scleroderma. 145 83

Growth of epithelial ovarian cancer is influenced by several factors including transforming growth factor-alpha and transforming growth factor-beta, macrophage colony stimulating factor, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, c-erb B-2 (HER-2/neu), and mutant p53. Continued expression of the epidermal growth factor receptor, new expression of c-fms, and overexpression of HER-2/neu are associated with a poor prognosis. A number of cytokines have been used to treat patients with ovarian cancer, including interferon-alpha, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2. Judging from preclinical models, interferon-gamma may be more active than interferon-alpha against human ovarian cancer. Although tumor necrosis factor-alpha can stimulate proliferation of some ovarian cancers, the cytotoxic activity of tumor necrosis factor-alpha has been amplified ex vivo by inhibitors of protein synthesis. Similar heterogeneity exists with regard to interleukin-1 where stimulation or inhibition of cell proliferation has been observed. Tumor-infiltrating lymphocytes from ascites fluid contain cells capable of major histocompatibility complex-restricted and major histocompatibility complex-nonrestricted cytotoxicity. Tumor-infiltrating lymphocytes and interleukin-2 have been combined with cytotoxic chemotherapy to treat advanced or recurrent disease. Bispecific monoclonal antibodies that react both with T cells and ovarian tumor cells have produced tumor inhibition in human tumor xenografts. Immunotoxins that contain OVB3 and pseudomonas exotoxin have been evaluated in a phase I clinical trial. Dose-limiting central neurotoxicity has been observed without tumor regression. A monoclonal antibody designated OVX1 has been developed against a high-molecular-weight mucinlike molecule associated with ovarian cancers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biology and therapy with biologic agents in gynecologic cancer. 145 11

Malignant gliomas are characteristically surrounded by marked gliosis. To assess whether glioma-derived products contribute to the proliferation of astrocytes, a feature of the gliosis response, we evaluated the influence of culture supernatants from malignant human glioma lines and tumor cyst fluids collected from two patients with glioblastoma multiforme on the proliferation of non-transformed adult human astrocytes. Both the culture supernatants and cyst fluids significantly increased DNA synthesis in astrocytes as assessed by a double immunofluorescence glial fibrillary acidic protein-bromodeoxyuridine technique. The net proliferative effect mediated by glioma cell line supernatants was tumor growth phase-dependent, being preferentially expressed during the logarithmic phase of glioma cell growth. Specific growth factor molecules and cytokines known to be secreted by gliomas (epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta, interleukin-6, and tumor necrosis factor-alpha) could not reproduce the mitogenic effects of the glioma-derived soluble factors. Cytokines which can induce DNA synthesis by adult human astrocytes in vitro, gamma-interferon and interleukin-1, were not detected in the culture supernatant of glioma lines used in this study. In conjunction with the documented effects of glioma products on endothelial and lymphoid cells, the current study suggests that soluble glioma products can contribute to the production of surrounding gliosis observed in vivo.
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PMID:Malignant glioma-derived soluble factors regulate proliferation of normal adult human astrocytes. 151 71

The rate of carbohydrate flux through phosphofructokinase (measured as the rate of [3-3H]glucose detritiation) was increased fourfold in rat liver parenchymal cells incubated with conditioned medium from lipopolysaccharide-stimulated adherent liver non-parenchymal cells. The rate was not affected in parenchymal cells incubated either with lipopolysaccharide directly or with conditioned medium from non-stimulated non-parenchymal cells. The stimulation of carbohydrate flux through phosphofructokinase by conditioned medium was not duplicated by peptide cytokines known to be released by lipopolysaccharide-activated liver non-parenchymal cells (interleukin-1, interleukin-6, tumor necrosis factor-alpha, and transforming growth factor-beta) or platelet activating factor. Furthermore, formation of the active conditioned medium was not prevented by inclusion of cycloheximide or dexamethasone to inhibit cytokine synthesis, or indomethacin or BW755c to inhibit arachidonic acid metabolism, during lipopolysaccharide-stimulation of the non-parenchymal cells. The results indicate that intercellular communication between lipopolysaccharide-stimulated liver non-parenchymal cells and parenchymal cells by soluble mediators is responsible for the stimulation of liver phosphofructokinase activity during endotoxin-induced shock. Studies to isolate and identify the factor(s) in the conditioned medium are currently in progress.
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PMID:Endotoxin stimulation of liver parenchymal cell phosphofructokinase activity requires nonparenchymal cells. 153 Nov 95

Animals subjected to immunostimulatory conditions exhibit reduced tissue levels of total cytochrome P450 and P450-dependent drug metabolism. We have investigated the possibility that depressed levels of two carcinogen-metabolizing cytochrome P450s may be due to decreased levels of the mRNAs encoding these enzymes by studying the effect of monocyte-derived cytokines on the induction of CYP1A1 and CYP1A2 mRNAs in isolated rat hepatocytes. Medium conditioned by activated human peripheral blood monocytes or by the U937 monocyte cell line suppressed the induction of both mRNAs by 2,3,7,8-tetrachlorodibenzo-p-dioxin, whereas beta-fibrinogen mRNA levels increased 30-40-fold. CYP1A2 mRNA induction was maximally inhibited more than CYP1A1 mRNA (approximately 95 and 65%, respectively), and lower concentrations of conditioned medium suppressed CYP1A2 mRNA induction (half-maximal at 1.9 and 3.1%, respectively). Low concentrations of recombinant interleukin-1 suppressed the inducer-dependent accumulation of both CYP1A1 and CYP1A2 mRNAs in a dose-dependent fashion (half-maximal at 2 and 0.5 units/ml, respectively), while two other monocyte-derived cytokines, interleukin-6 and transforming growth factor-beta, did not. Run-on transcription analysis demonstrated that conditioned medium and interleukin-1 rapidly suppressed the transcription rate of CYP1A1 and CYP1A2 in inducer-treated hepatocytes. The close correspondence between the reductions in CYP1A1 and CYP1A2 transcription rates and mRNA levels suggest that conditioned medium and interleukin-1 suppress the induction of these mRNAs principally through a transcriptional mechanism.
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PMID:Interleukin-1 beta suppresses the induction of P4501A1 and P4501A2 mRNAs in isolated hepatocytes. 156 64


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