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)

Mannose-binding protein (MBP) is a plasma protein synthesized by hepatocytes. MBP, a structural analogue of the complement component C1q, can activate complement via the classical pathway and plays an important role in host defence. Expression of the human MBP gene was studied using the human hepatoma cell line HuH-7. RNA extracted from HuH-7 cells was reverse-transcribed to cDNA, amplified by the polymerase chain reaction and analysed by Southern blot hybridization. MBP mRNA expression in HuH-7 cells was increased by interleukin-6 (IL-6), dexamethasone and heat shock, decreased by interleukin 1 (IL-1), and unaffected by interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta). Gel shift assays demonstrated Sp-1 binding sites in the 5' region of the gene, and formation of specific complexes between DNA and nuclear protein extracted from HuH-7 cells treated with IL-1 or IL-6. Human MBP is an acute-phase protein, and transcription of its gene is enhanced by IL-6, dexamethasone and heat shock but inhibited by IL-1. The actions of the cytokines appear to be mediated by specific transcription factors.
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PMID:Human mannose-binding protein gene is regulated by interleukins, dexamethasone and heat shock. 825 72

Hepatocytes respond to inflammatory stimuli by changing the synthesis and N-glycosylation of acute phase plasma proteins (APP). So far, interleukin (IL) 6, transforming growth factor beta (TGF beta), tumor necrosis factor alpha (TNF) and IL-1 have been found to control N-glycosylation patterns of APP. Cytokines either increased (type I) or decreased (type II) the ratio of bi-relative to more branched N-glycans on APP. In this study, we describe the effect of leukemia inhibitory factor (LIF), interferon gamma (INF gamma) and dexamethasone (dex) on production of alpha 1-protease inhibitor (PI) and alpha 1-antichymotrypsin (ACT) and on glycosylation of PI in the human hepatoma cell line HepG2. Cytokines and dex were used separately and in various combinations including also IL-6 and TGF beta. Production of the antiproteases was quantitated by immunoelectrophoresis of the proteins accumulated in the culture medium. Glycosylation pattern of PI was assessed by crossed immunoaffinity electrophoresis (CIAE) with Concanavalin A (Con A) as a ligand. The production of ACT and PI was increased by LIF, decreased by INF gamma and unaffected by dex. LIF and INF gamma each like IL-6, decreased PI-Con A reactivity while dex like TGF beta enhanced PI-Con A reactivity. Combination of dex with LIF yielded additive effects while combination of dex with either INF gamma, L-6 or TGF beta acted synergistically on PI-Con A reactivity. Combinations of multiple cytokines and dex produced additive, inhibitory or synergistic effects. The type of glycosylation profile of PI secreted by HepG2 cells depended on the composition and amounts of interacting cytokines and dex.
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PMID:Leukemia inhibitory factor, interferon gamma and dexamethasone regulate N-glycosylation of alpha 1-protease inhibitor in human hepatoma cells. 839 65

Mouse interferon gamma (IFN-G) markedly suppressed 7-ethoxyresorufin o-deethylase (EROD) activity when added at the same time as TCDD in mouse primary hepatocyte cultures. IFN-G, however, had no effect on EROD induction by TCDD in Hepa-1 cells, a mouse hepatoma cell line, or Hepa-1 cells cocultured with Kupffer cells when added directly to the culture. EROD induction by TCDD in Hepa-1 cells was suppressed when cells were cultured with IFN-G pretreated mouse hepatocytes conditioned media. The magnitude of suppression was related to the dose of IFN-G and the density of hepatocytes used for the preparation of the conditioned media. Treatment of the monoclonal antibody against IFN-G to the conditioned media did not block the suppression of EROD induction. The suppressive effect of IFN-G pretreated hepatocytes conditioned media on EROD induction, however, was blocked when the conditioned media was heated or treated with trypsin. These results suggested that IFN-G pretreated mouse hepatocytes may release a soluble protein factor(s) which suppressed the EROD induction by TCDD in Hepa-1 cells.
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PMID:Mouse interferon gamma pretreated hepatocytes conditioned media suppress cytochrome P-450 induction by TCDD in mouse hepatoma cells. 849 6

Hepatitis B virus (HBV) DNA contains consensus elements for transactivating proteins whose binding activity in other systems is regulated by inflammatory cytokines. Because HBV replicates within an environment of provoked inflammation, we speculated that the HBV core/pregenomic promoter may be regulated by cytokines produced in response to infection. To evaluate this hypothesis, the HBV core/pregenomic (C/P) promoter and associated cis-acting elements were placed upstream of a luciferase-encoding plasmid. This reporter construct was transfected into cytokine-sensitive hepatoma cells permissive for HBV replication, which were exposed to stimulated mononuclear cell-conditioned medium or human recombinant cytokines. Conditioned medium reduced luciferase expression by 80%. Tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and interferon alfa (IFN-alpha) each reduced luciferase activity by 40%. Combinations of TNF-alpha and interferons mimicked the extent of conditioned medium inhibition. Non-specific effects from diminished cellular viability or growth were not responsible for decreased luciferase activity. Retention of HBV DNA 330 basepairs upstream of the C/P transcription start site was required to maintain the TNF-alpha effect. A 60% reduction in HBV replicative forms within intracellular core particles was demonstrated with TNF-alpha treatment of Hep G2 cells stably transfected with HBV DNA. The inhibitory action of these cytokines implicates a noncytolytic mechanism by which antigen-nonspecific immune responses in part regulate HBV replication in infected hepatocytes. This function may be beneficial in accelerating viral clearance, but in alternative circumstances could contribute to viral persistence by attenuating immunogen recognition.
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PMID:Cytokine inhibition of the hepatitis B virus core promoter. 855 37

The cytoplasmic domain of the receptor for interleukin 10 (IL-10R) contains two box 3 sequence motifs that have been identified in the signal-transducing receptor subunits for IL-6-type cytokines and noted to be required for activating STAT3 and inducing transcription through IL-6-responsive elements. To determine whether the IL-10R has signaling functions similar to IL-6R in cells normally expressing these receptors, leukocytes of the B-, T-, and NK-cell lineages were treated with either cytokine. Both cytokines activated factors that bound to the sis-inducible element and included STAT1 and STAT3. The cell response to IL-10 characteristically differed from that to IL-2/IL-15, IL-4, and interferon gamma. The signaling capabilities of the IL-10R for activating specific STAT proteins and inducing gene transcription were defined by reconstitution of receptor functions in transfected tissue culture cells. COS-1 cells, co-expressing the human IL-10R and individual STAT proteins, confirmed a preference of the IL-10R for STAT3 and STAT1. Unlike many hematopoietin receptors, the IL-10R did not detectably activate STAT5. The IL-10R, together with reporter gene constructs containing different IL-6-responsive gene elements, reconstituted in hepatoma cells an induction of transcription by IL-10 that was comparable to that by IL-6. This regulation could not be appreciably modified by enhanced expression of STAT proteins. The similar actions of IL-10R and IL-6R on the induction of endogenous IL-6-responsive genes were demonstrated in hepatoma cells stably expressing the IL-10R. These receptor functions required the presence of the box 3 motifs, as shown by the analysis of the mouse IL-10R constructs containing progressively truncated cytoplasmic domains. The data demonstrate that the IL-10R, unlike other members of the interferon receptor family, is highly effective in recruiting the signaling pathways of IL-6-type cytokine receptors.
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PMID:Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements. 866 28

An increasing number of hepatic resections are being performed as potentially curative surgery for malignant liver neoplasms. Hepatectomy and subsequent liver regeneration produce a local environment that enhances growth of microscopic residual tumor. To determine if pretreatment with murine interferon gamma (IFN-gamma) can protect against such enhanced tumor growth, Buffalo rats were randomized to receive a 3-day treatment of IFN-gamma (50,000 U/qD intraperitoneally) or saline. Groups then underwent intrasplenic injection of 10(6) Morris hepatoma cells, followed 1 hour later by sham (control) or partial hepatectomy (PH) of 70%. PH significantly enhanced tumor growth within the liver (control, 8 +/- 3 nodules per liver; PH, 73 +/- 12 nodules per liver; P < .001). This enhancement was attenuated by prior administration of IFN-gamma IFN-gamma/PH, 16 +/- 3; P < .001 vs. PH). Growth factor release and liver regeneration were not affected significantly by pretreatment with IFN-gamma. The effect of IFN-gamma on tumor growth is associated with a significant enhancement of Kupffer cell (KC)-mediated tumoricidal activity (percentage of specific lysis, 55 +/- 10% control, 78 +/- 11% IFN-gamma, P < .01) but not lymphocyte-mediated tumoricidal activity. Because microscopic residual disease may be present after hepatectomies for cancer, IFN-gamma may be useful agent in retarding growth of residual tumors.
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PMID:Interferon gamma protects against hepatic tumor growth in rats by increasing Kupffer cell tumoricidal activity. 869 Apr 7

Costimulation mediated by costimulatory molecules, such as B7-1 and B7-2, which are ligands for the CD28/cytolytic T lymphocyte associated antigen (CTLA)-4 counter-receptor, plays an important role in the induction of T cell-mediated antitumor immunity. We investigated the expressions of B7-1, B7-2, and human leukocyte antigen (HLA) class I in seven human hepatocellular carcinoma (HCC) cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometric analysis. RT-PCR showed that all these human HCC cell lines were positive for B7-1 and B7-2 at the messenger RNA (mRNA) level. Flow cytometric analysis revealed that they all expressed B7-1, B7-2, and HLA class I on the cell surface. However, the expression levels of B7-1 and B7-2 were very low whereas those of HLA class I were high. B7-1 and B7-2 expression could be increased by treatment with interferon alpha and interferon gamma in a dose-dependent manner, although the expression levels of B7-1 and B7-2 after interferon treatment remained low. By transfecting Hep3B cells with a plasmid containing human B7-1 complementary cDNA (cDNA), we were able to establish Hep3B cell lines strongly expressing B7-1. From mixed lymphocytes and tumor cultures analysis, the primary cytolytic activity against parental Hep3B cells could be induced effectively by B71-transfected Hep3B cells. These findings suggested that B7-1 gene transfer is the best way to induce strong expression of this molecule and this might be useful for immuno-gene therapy against human HCC.
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PMID:Expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86) on human hepatocellular carcinoma. 914 26

We isolated an 18-kilobase (kb) genomic selenoprotein P clone from a human placenta library and cloned, sequenced, and characterized the 5'-flanking region of the human selenoprotein P gene. Sequence analysis revealed an intron between base pairs (bp) -13 and -14 upstream of the ATG codon and another one between bp 534 and 535 of the coding region. The major transcription start site of selenoprotein P in human HepG2 hepatocarcinoma cells was mapped to bp -70 by 5'-rapid amplification of cDNA ends and by primer extension. 1.8 kb of the 5'-flanking sequence were fused to a luciferase reporter gene. They exhibited functional promoter activity in HepG2 hepatocarcinoma and Caco2 colon carcinoma cells in transient transfection experiments. Treatment of transfected HepG2 cells with the cytokines interleukin 1beta, tumor necrosis factor alpha, and interferon gamma repressed promoter activity. Nuclear extracts of interferon gamma-treated cells bound to a signal transducer and activator of transcription response element of the promoter in gel retardation experiments. By transfection of promoter-deletion constructs, a TATA box and a putative SP1 site were identified to be necessary for selenoprotein P transcription. These data indicate that the human selenoprotein P gene contains a strong promoter that is cytokine responsive. Furthermore, selenoprotein P, secreted by the liver, might react as a negative acute phase protein.
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PMID:Cloning and characterization of the human selenoprotein P promoter. Response of selenoprotein P expression to cytokines in liver cells. 936 Oct 18

To explore the mechanisms of immuno-modulatory activities of bleomycin, we investigated interferon gamma (IFN gamma) mRNA expression, tumor necrosis factor alpha (TNF alpha) production, nitric oxide (NO) production and macrophage tumoricidal activities in rats bearing KDH-8 hepatoma cells, which secreted a large amount of transforming growth factor beta (TGF beta), and these processes in KDH-8 tumor-bearing rats treated with bleomycin. We found that IFN gamma mRNA expression, TNF alpha production, NO production and macrophage cytotoxic activities were lower in the KDH-8-bearing rats than in normal rats. On the other hand, low-dose bleomycin restored the macrophage cytotoxic activities, NO production, IFN gamma mRNA expression and TNF alpha production in the KDH-8-bearing rats. In vitro experiments showed that KDH-8-derived TGF beta decreased the IFN gamma mRNA expression and TNF alpha production in splenocytes, and NO production in peritoneal macrophages. These results suggest that low-dose bleomycin restored the cytokine production and macrophage tumoricidal activities in the KDH-8-bearing rats by decreasing KDH-8-derived TGF beta.
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PMID:Restoration of macrophage tumoricidal activity by bleomycin correlates with the decreased production of transforming growth factor beta in rats bearing KDH-8 hepatoma cells. 939 Jan 97

Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions, hepatocytes themselves are generally considered only targets but not producers of these important mediators. In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT-PCR. Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), macrophage colony-stimulating factor (M-CSF), oncostatin-M (OSM), intercellular adhesion molecule (ICAM-1), interleukin 4 (IL-4), IL-5, IL-7, IL-10, IL-11, IL-12 and IL-6 receptor (IL-6R). At the same time the expression of IL-1, IL-2, IL-3, IL-6, CD40 ligand and IL-2R genes was not detected. It was concluded that hepatocytes are potential producers of a variety of cytokines, some of them being able to regulate hepatocellular functions directly, while others are important regulators of leukocyte activity. Thus, on the one hand, hepatocytes may express autoregulatory cytokines and on the other hand, influence the functions of other liver cells like Kupffer, Ito or endothelial cells. Due to their large amount, liver parenchymal cells could be an important source of sytemically acting pro- and anti-inflammatory and other regulatory cytokines.
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PMID:HepG2 human hepatoma cells express multiple cytokine genes. 1008 37


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