Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of RU 41.740 on natural killer (NK) cell cytotoxicity from normals and patients with advanced hepatocellular carcinoma (HCC) was studied. RU 41.740-treated normal enriched large granular lymphocytes (LGLs) showed increased cytotoxic activity against 51Cr-labelled K562 cells. Although the drug increased the cytotoxic activity of LGLs from HCC patients, these results were not statistically significant. As LGLs have been shown to release interleukin-1 (IL-1) after suitable stimulation the effects of RU 41.740 on production of this cytokine from both monocytes and LGLs was studied. The drug stimulated IL-1 release from normal cells but monocyte and LGL IL-1 production from HCC patients was not influenced by RU 41.740 by RU 41.740. It is concluded, therefore, that although RU 41.740 can stimulate natural cytotoxicity and IL-1 production by normal LGLs, it is unable to correct the defect which exists in these functions in patients with large mass tumours.
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PMID:The effect of RU 41.740 (Biostim) on the production of interleukin-1 by monocytes and enriched large granular lymphocytes in normals and patients with hepatocellular carcinoma. 300 5

SK hepatoma cells and SK hepatoma conditioned media contain an 18,000-dalton factor which is pyrogenic, stimulates collagenase and prostaglandin production in skin and synovial fibroblasts, induces bone resorption, and stimulates the proliferation of murine thymocytes. These results are consistent with the finding that this tumor cell line produces interleukin 1 [Doyle, M. V., Brindley, L., Kawasaki, E., & Larrick, J. (1985) Biochem. Biophys. Res. Commun. 130, 768-773] since all these activities have been associated with this cytokine. Greater than 80% of the cellular activity has a molecular weight of 30,000, while in contrast, greater than 80% of the activity in the tumor-conditioned media has a molecular weight of 18,000. When active material from the cells is incubated with trypsin, this high molecular weight material is completely converted into an active 18,000 molecular weight species. The isoelectric point of all active material is always between pI 4.0 and 5.1, regardless of molecular weight. All of these results are consistent with the hypothesis that active, high molecular weight interleukin 1 alpha is first synthesized and stored by the tumor cell. This cytokine is then cleaved by a trypsin-like protease to an active, lower molecular weight species which can be secreted into the media.
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PMID:Production of interleukin 1 by SK hepatoma tumor cells. 302 59

Interleukin 6 (IL6) is the new definition of a group of cytokines previously named according to their biological activity, e.g. B cell stimulatory factor 2 (BSF-2), hybridoma plasmocytoma-growth factor (HGF), interferon-beta 2 (IFN-beta 2), hepatocyte stimulating factor (HSF). It has recently been suggested that IL6 may represent the major mediator of acute-phase protein response whereas IL1 beta and TNF-alpha could play a minor role. We compared the effect of the three cytokines on hepatic protein synthesis by performing in vitro as well as in vivo experiments. Human hepatoma cells (PLC/PRF5) were exposed to each cytokine separately for 20 h, and the effect was then studied at the protein and RNA level. All three cytokines reduced albumin and increased C3 and ceruloplasmin biosynthesis. The cytokines induced the same effect at the RNA level indicating that the modulation was pretranslational. The effect of the cytokines was specific since actin gene expression was not changed; furthermore the effect was blocked by specific antibodies against the cytokines. The effect of the single cytokines was dose and time dependent, and quantitatively comparable. None of the cytokines was able to alter alpha 1-anti-trypsin synthesis. In vivo experiments with mice showed that IL1 beta and TNF-alpha both induce serum amyloid A (SAA) mRNA in the mouse liver and increase factor B (Bf) gene expression. Human recombinant IL6 induced SAA gene expression and it also had a weak positive effect on Bf gene expression after i.p. injection. These data demonstrate that the three cytokines studied are quantitatively and qualitatively comparable, and that all three are probably involved in acute-phase protein response.
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PMID:Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor-alpha. 313 37

Several pro-inflammatory cytokines have been shown to be important in the modulation of the procoagulant response. However, what role these cytokines may have in the regulation of coagulation inhibitors is poorly understood. While the hepatocyte is a primary site of synthesis for the anticoagulant protein C and S, it is also a major target cell for the proinflammatory cytokine, IL-6. We have found that stimulation of HepG-2 hepatoma cells with IL-6 (5 ng/ ml) significantly increased the production of the anticoagulant cofactor, protein S, in both a time and dose dependent fashion. This increase was seen at both the RNA and protein level. A mouse monoclonal neutralizing antibody to human IL-6 suppressed the IL-6 effect in a concentration dependent fashion. IL-6 also increased the release of the C4b-binding protein but had no effect on protein C production. When combined with either dexamethasone or soluble IL-6 receptor, the IL-6 response was significantly enhanced. Oncostatin M, a functionally related cytokine, had a similar effect while other related cytokines, IL-11 and leukemia inhibitory factor, only had a marginal effect. IL-1, TGF-beta, and TNF-alpha had no significant effect on protein S production. These results indicate that IL-6 may play an important regulatory role in the anti-coagulant pathway.
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PMID:IL-6 upregulates protein S expression in the HepG-2 hepatoma cells. 748 9

Increasing evidence implicates free radical processes in the pathogenesis of ethanol-induced liver injury. One of the antioxidant defense systems in mammalian cells is the mitochondrial enzyme manganese superoxide dismutase (MnSOD). MnSOD activity is increased by agents that cause oxidative stress. One such agent is the cytokine tumor necrosis factor-alpha (TNF). Increased serum/tissue TNF levels have been observed in alcoholic liver disease, and TNF has been postulated to play a role in ethanol-induced liver injury. Substantial evidence suggests that ethanol itself can cause oxidative stress. In order to investigate the mechanism of the cellular adaptive response to ethanol-induced oxidative stress, the effects of short-term ethanol exposure on MnSOD RNA, protein, and activity were determined in a human hepatoma cell line (HepG2). We found that exposure to ethanol (25 mM concentration) for 72 h increased the protein level and enzyme activity of MnSOD. However, examination of the mRNA levels of the enzyme showed no corresponding increase. Long-term administration of ethanol (10 weeks) did not significantly increase MnSOD protein and MnSOD activity. MnSOD activity was significantly increased by TNF. Thus it appears that both TNF and ethanol are capable of increasing MnSOD activity presumably via enhanced oxidative stress. However, unlike TNF, acute ethanol administration increases the activity of MnSOD without increasing MnSOD mRNA. The increase in MnSOD after a short-term dose of ethanol is diminished with repeated ethanol administrations. These findings are compatible with the view that chronic exposure to ethanol suppresses the cellular adaptive response to oxidative stress. If this adaptive response of MnSOD is lessened, it may have implications in the increased toxicity due to prolonged ethanol exposure.
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PMID:Differential regulation of manganese superoxide dismutase activity by alcohol and TNF in human hepatoma cells. 748 13

A stromal protein, designated restrictin-P, that specifically kills plasma-like cells was purified to homogeneity and shown to be identical with activin A. The specificity to plasma-like cells stemmed from the ability of restrictin-P/activin A to competitively antagonize the proliferation-inducing effects of interleukin (IL) 6 and IL-11. Restrictin-P further interfered with the IL-6-induced secretion of acute phase proteins by HepG2 human hepatoma cells and with the IL-6-mediated differentiation of M1 myeloblasts. A competition binding assay indicated that restrictin-P did not interfere with the binding of IL-6 to its receptor on plasma-like cells, suggesting that it may act by intervening in the signal transduction pathway of the growth factor. Indeed, concomitant addition of restrictin-P and IL-6 to cytokine-deprived B9 hybridoma cells was followed by sustained overexpression of junB gene until cell death occurred, while IL-6 alone caused a transient increase only. This altered response to IL-6 stimulation was accompanied by a moderate increase in STAT protein activation. Thus, in this study, we identified the plasmacytoma growth inhibitor, restrictin-P, as being activin A of stromal origin. It is shown that activin A is an antagonist of IL-6-induced functions and that it modifies the IL-6 signaling pattern.
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PMID:The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin 6 and interleukin 11. Identification as a stroma-derived activin A. 749 3

The rat hepatoma cell line, H-35, responds to IL-1- and IL-6-type cytokines by an increased transcription of specific acute phase plasma protein (APP) genes. Transforming growth factor-beta (TGF-beta), although ineffective on its own in regulating APP genes, modulates the action of the IL-type cytokines. In growing cultures, the IL-6 and IL-11 stimulation of thiostatin and hemopexin is enhanced by TGF-beta, whereas the stimulation of other APP is reduced. The effects of leukemia inhibitory factor, ciliary neurotrophic factor, IL-1, and TNF-alpha are generally attenuated by TGF-beta. Enhancement by TGF-beta of the IL-6-induced response can be explained in part by the fact that TGF-beta, in combination with dexamethasone, stimulates severalfold the expression of the 80-kDa ligand-binding subunit of IL-6R. Serum deprivation of H-35 cells for 3 days leads to an enhanced basal and cytokine-stimulated level of APP gene expression concomitant with a loss of the divergent regulatory effect of TGF-beta. In growth-arrested H-35 cells, TGF-beta still enhances the IL-6R expression but it attenuates all IL-6 effects on APP genes. These data suggest that TGF-beta influences the signal transduction of the IL-type cytokines by separate mechanisms and that the manifestation of the TGF-beta action is modulated by the growth state of the cell culture.
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PMID:Divergent transforming growth factor-beta effects on IL-6 regulation of acute phase plasma proteins in rat hepatoma cells. 750 21

We have reported previously that the phosphoprotein pp63, an acute phase protein, which has been recently identified as the rat fetuin, was capable of blocking the mitogenic effect of insulin on the rat Fao hepatoma cell line, without affecting metabolic effects of the hormone. Only the phosphorylated form of the protein has been shown to exhibit both anti-tyrosine kinase and growth inhibitory properties. In this study, we used the FTO-2B rat hepatoma cell line to analyze the mechanisms involved in the control of synthesis and/or phosphorylation of pp63. For this purpose, we investigated the action of effectors known to modulate hepatic functions, such as cytokines (interleukin (IL)-1 beta and IL-6), which regulate the production of acute phase proteins, and insulin, which elicits profound effects on hepatocyte metabolism. Here, we demonstrate that IL-1 beta diminished markedly the pp63 production by affecting its mRNA transcription and that the cytokine was able to modify the N-glycosylation process of the protein. In contrast, insulin did not affect the biosynthesis of pp63 but dramatically decreased its extent of phosphorylation.
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PMID:Insulin and interleukin-1 differentially regulate pp63, an acute phase phosphoprotein in hepatoma cell line. 751 65

The receptor for granulocyte colony stimulating factor (G-CSFR) and chimeric receptors consisting of the extracellular domain of G-CSFR and the transmembrane and cytoplasmic domain of the leukemia inhibitory factor receptor, gp130, or c-mpl function as homodimeric complexes. These receptors mediate a similar stimulation of gene transcription via separate regulatory elements of acute phase plasma protein genes. To identify the receptor regions within the cytoplasmic domains necessary for transcriptional regulation, the receptors were transiently expressed in rat hepatoma cells. Each receptor form reconstituted G-CSF-induced expression of a chloramphenicol acetyltransferase gene construct containing the cytokine response element of the rat alpha 1-acid glycoprotein gene. This regulation required the presence of two conserved sequence motifs (referred to as box 1 and box 2) in the cytoplasmic domains of each receptor. With the exception of G-CSFR-MPL chimera, the receptors also mediated a similarly high stimulation via the IL-6 response element of the rat beta-fibrinogen and hemopexin genes. Regulation of the IL-6 response element required, however, in addition to boxes 1 and 2, a third sequence motif (box 3). This motif is absent in the cytoplasmic domain of c-mpl, possibly explaining its inability to activate the IL-6 response element. When cells which express receptor forms with prominent box 3 function were treated with suramin, a ligand-independent gene stimulation via the IL-6 response element was observed. The suramin effect probably involves a receptor dimerization mediated by the extracellular G-CSFR domain and by the intracellular regions that include box 3.
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PMID:Signaling by the cytoplasmic domain of hematopoietin receptors involves two distinguishable mechanisms in hepatic cells. 751 79

We have studied transcription factors that are coupled to the activation of cytokine receptors in liver and in mammary epithelial cells. Interleukin-6 (IL-6) causes the rapid activation of the acute-phase response factor (APRF) in the liver of animals during acute inflammation and in cultured human hepatoma cells (HepG2) and induces the transcription of the acute-phase protein genes, e.g. alpha 2-macroglobulin (alpha 2-M). In the mammary gland and in cultured HC11 mammary epithelial cells, milk protein genes, e.g. beta-casein, are induced by the lactogenic hormones, insulin, glucocorticoids, and PRL. The induction of the beta-casein gene promoter is preceded by the activation of the mammary gland factor (MGF). We have compared the DNA binding sequences of APRF and MGF, 5'-CTTCTT/GGGAATT-3', and have found that they coincide in 11 of 12 positions. Bandshift experiments and oligonucleotide competition experiments showed that both factors, MGF and APRF, are able to bind to the IL-6 response element of the alpha 2-M gene promoter and to the lactogenic hormone response element of the beta-casein gene promoter with very similar specificities. Partial proteolytic digestion of APRF and MGF DNA complexes yielded similar clipping patterns. The UV cross-linked DNA complexes of both transcription factors were of the same apparent molecular mass. IL-6 activation of APRF in HepG2 cells can be observed within minutes. MGF induction by PRL in HC11 cells occurs with similar kinetics. The synergistic action of glucocorticoids and PRL is necessary for the induction of the beta-casein gene, but PRL is sufficient for MGF activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mammary gland factor activated by prolactin on mammary epithelial cells and acute-phase response factor activated by interleukin-6 in liver cells share DNA binding and transactivation potential. 751 23


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