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)

Substance P (SP) and lipopolysaccharide (LPS) stimulated interleukin-6 (IL-6) gene expression, as well as IL-6 protein secretion in the human astrocytoma cell line U373 MG. Staurosporine, an inhibitor of protein kinase C (PKC), entirely blocked SP- but not LPS-induced IL-6 release. In addition, the down regulation of PKC inhibited the SP response and only marginally altered LPS activation. Differently from SP, LPS-induced IL-6 release was markedly reduced by W7, a calmodulin antagonist. Moreover, SP interacted in a synergistic manner with LPS. Thus, neural (SP) and bacterial (LPS) mediators stimulate U373 MG IL-6 release via distinct, though not antagonistic, activation pathways.
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PMID:Interleukin-6 production by U373 MG, a human astrocytoma cell line: different pathways involved in substance P and lipopolysaccharide activation. 754 Oct 52

The immunosuppressive cyclic undecapeptide, cyclosporin A, inhibited the binding of [125I]substance P to tachykinin NK1 receptors expressed by human IM-9 lymphoblastoid cells, U-373 MG human astrocytoma cells and guinea pig lung parenchyma with IC50 values of 425 +/- 58, 783 +/- 180, and 784 +/- 163 nM respectively. The dihydro derivative of cyclosporin A (dihydro-cyclosporin A) was an equally effective inhibitor, but the O-acetylated derivative (cyclosporin A-OAc) was 3-4 fold less potent. The cyclosporin compounds also inhibited [125I]neurokinin A binding to human NK2 receptors with potencies slightly less than at NK1 sites. In contrast, they were 8-20-fold less effective inhibitors of [125I]MePhe7-neurokinin B binding to guinea pig NK3 receptors (p < 0.001). Thus, the cyclosporin A compounds showed selectivity for NK1 and NK2 receptors. The structure-activity pattern for the effects of cyclosporin A compounds at tachykinin receptors differs from the pattern previously described for their immunosuppressive activity. All three compounds inhibited substance P induced interleukin-6 (IL-6) secretion from U-373 MG astrocytoma cells with potencies similar to their NK1 receptor binding affinities. In addition, cyclosporin A blocked substance P induced phosphatidylinositol (PI) turnover in U-373 MG cells without blocking the corresponding response to histamine. This novel pharmacological profile of the cyclosporin A compounds as NK1 receptor antagonists does not appear to correlate with other known in vitro cyclosporin A functions.
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PMID:Cyclosporin A is a substance P (tachykinin NK1) receptor antagonist. 755 12

We have investigated the roles of tyrosine kinase and protein kinase C activity in interleukin-1 beta-induced interleukin-6 production, using the U373 human astrocytoma cell line as a model system for astrocytes. Compounds known to inhibit tyrosine kinases were tested for effects on interleukin-6 production in U373 cells stimulated with interleukin-1 beta. Complete to nearly complete inhibition of interleukin-1 beta-induced interleukin-6 production was observed with the flavonoids genistein and quercetin, the bisindole alkaloids staurosporine and K-252a, or the tyrphostin AG879. Herbimycin A was a potent inhibitor but did not induce complete inhibition at saturating dose. Calphostin C, an inhibitor of protein kinase C, also completely inhibited interleukin-6 production. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate induced interleukin-6 production, and treatment with a combination of this phorbol ester and interleukin-1 produced synergistic stimulation. Prolonged exposure to phorbol ester eliminated subsequent stimulation by phorbol ester but only partially decreased interleukin-1-induced interleukin-6 and had no effect on the activities of selected inhibitors including calphostin C. We conclude that tyrosine kinase activity is essential for interleukin-1-induced interleukin-6 production in U373 astrocytoma cells and that activity of a phorbol ester-insensitive, atypical protein kinase C isozyme may also be involved.
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PMID:Tyrosine kinase activity is essential for interleukin-1 beta--stimulated production of interleukin-6 in U373 human astrocytoma cells. 759 43

We previously reported that interleukin-4 (IL-4) inhibited proliferation of a human astrocytic cell line derived from non-neoplastic adult cortex. To determine whether this effect was receptor-associated and/or limited to only non-neoplastic astrocytes, we examined IL-4 responsiveness and receptor expression in human astrocytic cell lines derived from three different sources: non-neoplastic cerebral cortex (lines P1N, P2N, W3N); neoplastic low grade astrocytoma (LGA) (lines FRLGA, RTLGA); and highly malignant glioblastoma multiforme (GBM) (lines STTG1, CRTG2, WITG3, RUTG4). All lines except RUTG4 GBM expressed IL-4 receptor mRNA. Proliferation and DNA synthesis were markedly suppressed by IL-4 in a dose- and time-dependent manner in all non-neoplastic astrocyte and LGA lines, but not (0/4) GBM. This negative growth-regulatory effect of IL-4 was blocked by specific antibody to human IL-4 receptor but not by irrelevant IgG. In contrast, IL-4 stimulated interleukin-6 (IL-6) secretion in non-neoplastic astrocytes and LGA as well as in GBM cells expressing IL-4 receptor; secretion was undetectable in RUTG4 GBM which did not express receptor. These results indicate that: (i) responsiveness to IL-4 occurs in both non-neoplastic and neoplastic human astroglia; (ii) responsiveness is associated with IL-4 receptor expression; and (iii) sensitivity to negative growth signalling by IL-4 occurs selectively in astrocytes from non-neoplastic cortex or low grade neoplasia but not from highly malignant GBM.
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PMID:Human astrocyte growth regulation: interleukin-4 sensitivity and receptor expression. 764 50

Inflammatory cytokines (interleukin 1 alpha, 1 beta and tumor necrosis factor-alpha) induce the formation of nitrite by C6 astrocytoma cells in a manner that was blocked by inhibitors of NO synthase such as NG-monomethylarginine. They increase the formation of cGMP. This action was potentiated by isobutylmethylxanthine and was inhibited by NG-monomethylarginine. Interleukin-6 and interferon-gamma were inactive. It is concluded that the nitridergic signalling pathway is active in C6 cells and is a major target for inflammatory cytokines.
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PMID:IL1 and TNF alpha induce cGMP formation in C6 astrocytoma cells via the nitridergic pathway. 768 59

The effect of measles virus (MV) infection on mRNA expression and protein synthesis of cytokines in human malignant glioma cell lines (D-54 and U-251) was investigated. Primary MV infections led in both cell lines to the induction of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interferon-beta (IFN-beta), and tumor necrosis factor-alpha (TNF-alpha). In contrast, persistently infected astrocytoma lines continually produced IL-6 (two out of 12 lines high levels) and IFN-beta, whereas only 1 out of 12 lines synthesized TNF-alpha and none IL-1 beta. The pathways for induction of IL-1 beta and TNF-alpha expression were not suppressed by the persistent MV infection, since IL-1 beta and TNF-alpha could be induced by external stimuli like diacylglycerol analog plus calcium ionophore. Interestingly, persistently infected astrocytoma cells synthesized considerably higher levels of IL-1 beta and TNF-alpha than uninfected cells after additional external induction. These results suggest that in the central nervous system (CNS) of SSPE patients a percentage of persistently infected astrocytes may continually synthesize IL-6 and IFN-beta, and in the presence of additional external stimuli, as possibly provided by activated lymphocytes, might overexpress the inflammatory cytokines IL-1 beta and TNF-alpha. This may be of pathogenetic significance in CNS diseases associated with persistent MV infections.
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PMID:Differential induction of cytokines by primary and persistent measles virus infections in human glial cells. 768 10

We analyzed the response of human astrocytoma cell line U373-MG to various cytokines by measuring the production of interleukin-6 (IL6) mRNA and cytokine protein. Interferon gamma (IFN gamma), transforming growth factor beta 1 (TGF-beta 1), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-colony-stimulating factor (G-CSF) did not induce IL6 mRNA production; however, IL6 mRNA expression and protein production was strongly induced by IL1 alpha and to a lesser extent by IFN alpha. The IL6 mRNA expression induced by IL1 alpha was potentiated by TGF-beta 1 and IFN alpha and slightly decreased by IFN gamma. The potentiation of cytokine mRNA accumulation by TGF-beta 1 was both time- and concentration-dependent. Induction of IL6 mRNA by IL1 alpha was optimally potentiated either if U373-MG cells were pretreated with TGF-beta 1 or if TGF-beta 1 was added within 30 min after stimulation with IL1 alpha. The potentiation of IL6 mRNA by TGF-beta 1 required de novo synthesis of an intermediate protein since treatment with cycloheximide abrogated the amount of mRNA enhanced by TGF-beta 1 without affecting IL1 alpha-driven mRNA production. Nuclear run-on analyses demonstrated increased transcriptional activity of the IL6 gene when stimulated with IL1 alpha in the presence of TGF-beta 1. However, actinomycin-D pulse chase experiments showed that TGF-beta 1 did not increase the stability of IL6 mRNA. Thus, in concert, the results demonstrate that TGF-beta 1 potentiates IL6 production in astrocytoma cells by promoting the transcriptional activity of the IL6 gene and requires coexpression of new proteins. Since cytokines can provide potent mitogenic signals to tumor cells, the results presented here further suggest that the antitumor effect of combination cytokine therapy might partly depend on heterotypic interactions between tumor cells and cytokines.
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PMID:Transforming growth factor beta-1 (TGF-beta 1) potentiates IL1 alpha-induced IL6 mRNA and cytokine protein production in a human astrocytoma cell line. 805 3

Tumor necrosis factor-alpha (TNF-alpha), a cytokine produced by astrocytes in vivo and in vitro, was tested for its effects on two malignant astrocytoma cell lines (A-172, U-87). Both lines were immunoreactive for glial fibrillary acidic protein, vimentin, Class I antigens, and interleukin-6. The lines differed in their expression of Class II and intercellular adhesion molecule-1 (ICAM-1) antigenic determinants: A-172 cells were negative for both Class II and ICAM-1 antigens, while U-87 cells were intensely positive for Class II and weakly positive for ICAM-1. When these astrocytoma cell lines were exposed to TNF-alpha, A-172 growth was stimulated while U-87 growth was inhibited. Furthermore, in U-87 cells, TNF-alpha enhanced both ICAM-1 and interleukin-1 beta (IL-1 beta) expression, and decreased immunoreactivity for transforming growth factor-beta (TGF-beta) protein. In contrast, in the presence of TNF-alpha, A-172 cells remained negative for IL-1 beta and TGF-beta, but showed an increased expression of ICAM-1. These results demonstrate that TNF-alpha can induce changes in growth rate, cytokine production, and surface antigen expression in malignant astrocytomas; however, the nature of these changes is dependent on the specific characteristics of these malignant astrocytomas. The resultant variability in the immunological microenvironment of these tumors may reflect differences in their growth potential.
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PMID:Differential effects of tumor necrosis factor-alpha on proliferation, cell surface antigen expression, and cytokine interactions in malignant gliomas. 809 40

Interleukin-6 (IL-6) has previously been shown to participate in neurodegenerative processes including Alzheimer's disease. However, the mechanisms leading to increased IL-6 expression in the brain remain largely unknown. We have studied the effects of synthetic ceramides and sphingomyelinase as possible regulators of IL-6 gene expression in a human astrocytoma cell line. The synthetic ceramides C2- and C6-ceramide as well as the enzyme sphingomyelinase were able to induce IL-6 gene transcription and protein synthesis in a dose-dependent manner with maximal IL-6 mRNA levels being reached after 4 h of ceramide treatment. We propose that the sphingomyelin pathway is part of the signal transduction cascade leading to IL-6 gene expression in astrocytes, and that this pathway may be involved in IL-6-mediated neurodegenerative processes.
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PMID:Stimulation of the sphingomyelin pathway induces interleukin-6 gene expression in human astrocytoma cells. 855 Aug 18

Cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) have previously been shown to participate in neurodegenerative processes including Alzheimer's disease. However, the molecular consequences of increased cytokine expression in the brain remain largely unknown. We have studied the effects of IL-1, IL-6 and TNF alpha on the expression of the acute-phase protein alpha 1-antichymotrypsin (ACT) in human astrocytoma cell lines. Both IL-1 and TNF alpha, but not IL-6, were able to induce ACT gene transcription and protein synthesis. The synthetic glucocorticoid dexamethasone enhanced cytokine-induced ACT mRNA expression and protein synthesis. We conclude that IL-1-induced expression of ACT may be part of the inflammatory response in the brain and may be involved in the pathology of Alzheimer's disease.
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PMID:IL-1 beta and TNF alpha, but not IL-6, induce alpha 1-antichymotrypsin expression in the human astrocytoma cell line U373 MG. 874 37


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