UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand the mechanisms responsible for lipopolysaccharide (LPS)-induced enhancement of angiotensinogen synthesis in the liver, studies were carried out in rats with repeated doses of LPS. The administration of sublethal dose (50 micrograms, i.p.) of LPS to rats resulted in increase in serum levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6), which attained their maximal levels by 1 and 2-4h, respectively. Serum levels of angiotensinogen and alpha 2-macroglobulin, a typical acute-phase protein in the rat, were also increased by a primary LPS challenge, and their maximal levels for the formation of TNF and IL-6 were delayed with peaks at 12 and 48 h, respectively. Repeated i.p. administration of LPS (50 micrograms/d) for 5 consecutive days induced a hyporesponsiveness to its subsequent administration in terms of increasing serum TNF, IL-6 and alpha 2-macroglobulin. In these LPS-tolerant rats, either LPS-induced elevation of angiotensinogen concentration in serum or angiotensinogen mRNA levels in liver was completely eliminated. Angiotensinogen synthesis in rat hepatoma H4 cells was enhanced in vitro by the addition of sera which had been collected 2 or 4 h after a primary injection of LPS, while not by sera collected from LPS-pretreated rats after a secondary LPS exposure. These results indicate that LPS-induced enhancement of angiotensinogen synthesis in the liver is desensitized in rats after repetitive LPS exposure, presumably by the failure of LPS-induced IL-6 production.
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PMID:Endotoxin-induced enhancement of angiotensinogen synthesis in the liver: decreased response following repeated endotoxin exposure. 750 88

We recently identified a gene that is induced by lymphocyte activation (ILA). The sequence of the full-length 1.4-kb cDNA characterized ILA as a new member of the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor family and the human homologue of the murine T-cell-specific receptor 4-1BB. The present study demonstrates ILA mRNA isoforms at 4.4, 4.0, and 1.8 kb in poly-A+ RNA from activated, but not from resting human peripheral blood T lymphocytes. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay was used to study tissue distribution and regulation of ILA expression. The gene was induced in T lymphocytes by phytohemagglutinin (PHA), phorbol myristate acetate (PMA), and antibody to CD3, in B lymphocytes by PMA and antibodies to cell surface Ig, and in blood monocytes by interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS), and PMA. In T lymphocytes, ILA mRNA was detectable 1.5 hours after stimulation, reached maximal levels at 8 hours, and declined to background levels by 48 hours. Induction of ILA mRNA required protein synthesis and was primarily due to increased transcription. Actinomycin D reduced ILA mRNA levels in activated lymphocytes 50% within 30 minutes, demonstrating a relatively short half-life of this mRNA. Analysis of nonlymphoid cells showed that ILA mRNA was not detectable in resting cells. However, in contrast to the lymphoid-specific expression of the murine 4-1BB gene, ILA was detected in nonlymphoid cells, including epithelial and hepatoma cells after stimulation with IL-1 beta. ILA was not detectable in several brain derived cell lines. The ILA cDNA encodes a 30-kD protein as demonstrated by in vitro translation, and this protein is immunoprecipitated by antisera that were raised against ILA peptides or a glutathione-S-transferase fusion protein. Flow cytometry showed expression of ILA protein on a subset of activated T or B lymphocytes. In conclusion, activation-dependent expression of ILA is found not only in T lymphocytes, but also in B lymphocytes, monocytes, and diverse nonlymphoid cell types.
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PMID:ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. 784 93

CCAAT/enhancer-binding proteins (C/EBPs) comprise a homologous group of transcriptional regulators that control liver and fat differentiation and are involved in regulating the expression of acute phase reactants during the host response to inflammation. GADD153, a unique member of the C/EBP family, has been proposed to act as a dominant negative inhibitor of other C/EBPs, but little is known about its expression in liver or its role in the processes described above. We have examined its expression during the acute phase response (APR) and have shown that like C/EBP beta and C/EBP delta, GADD153 mRNA is markedly induced in livers of rats treated with lipopolysaccharide to initiate the APR. Interestingly, its induction is temporally delayed relative to that of C/EBP beta and C/EBP delta but is similar to that of acute phase reactants shown to be regulated by C/EBPs. Footprint analysis of the GADD153 promoter showed binding of proteins in liver extracts of both untreated and lipopolysaccharide-injected rats to a putative C/EBP regulatory site. Gel shift analysis showed that although present constitutively, binding activity was increased in extracts from lipopolysaccharide-treated animals. Both C/EBP alpha and C/EBP beta were shown to contribute to the binding activity with the contribution by C/EBP beta increasing during the APR. Support for the functional role of this C/EBP-binding site and its interaction with C/EBPs in regulating GADD153 expression was obtained with cultured HepG2 hepatoma cells in which overexpression of C/EBP beta was found to transactivate expression of a plasmid containing the GADD153 promoter linked to a reporter gene. These findings suggest that the GADD153 gene is itself regulated by C/EBPs during the host response to inflammation and that GADD153 is likely to contribute to the regulation of other genes whose expression is altered during the APR.
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PMID:Induction of GADD153, a CCAAT/enhancer-binding protein (C/EBP)-related gene, during the acute phase response in rats. Evidence for the involvement of C/EBPs in regulating its expression. 778 52

Properdin is the only known positive regulator of the alternative pathway of complement activation. Northern blot analysis of cell lines derived from fibroblasts, B-cells, hepatoma cells, and cells of the monocyte-macrophage lineage revealed properdin expression only in the myelomonocytic cell line HL-60, in the monoblastic cell line U-937 and in the monocytic line Mono Mac 6. Culture of Mono Mac 6 cells for 24 h with phorbol 12-myristate 13-acetate, bacterial lipopolysaccharide and the cytokines interleukin-1 beta and tumour necrosis factor-alpha enhanced mRNA abundance, with the strongest effect (tenfold) being observed with the lipopolysaccharide. In contrast, recombinant interferon-gamma consistently halved properdin mRNA abundance. The same pattern was found for the secretion of properdin as detected by ELISA of Mono Mac 6 supernatants. The suppressive effect of interferon-gamma on properdin mRNA abundance was also demonstrated for primary blood monocytes. The data suggest that the expression and secretion of this complement regulatory protein by monocytes is differentially regulated by cytokines and link the immune response with alternative pathway activation.
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PMID:Expression of properdin in human monocytes. 811 26

Macrophage-like RAW 264 and H35 hepatoma cells grown under serum-free conditions exported putrescine and an unidentified diamine into the culture medium. Unlike putrescine, the unknown compound could be detected only extracellularly. Analyses of dansylated polyamine standards and mass spectroscopy confirmed that the unknown compound was cadaverine (1,5-diaminopentane). The cells were free of mycoplasma as evidenced by a negative result using a probe specific for prokaryotic rRNA. After prophylactic treatments with two different mycoplasmacidal agents, the cells continued to export cadaverine. Attempts to "infect" a noncadaverine-exporting cell line with culture medium and cell-free lysates proved unsuccessful, establishing that cadaverine was in fact a bona fide product of these mammalian cells. Cadaverine export by RAW 264 and H35 cells was stimulated by lipopolysaccharide and insulin, respectively. However, administration of exogenous ornithine caused cadaverine export to decrease significantly with concomitant increases in putrescine export. alpha-Difluoromethylornithine, a selective inhibitor of ornithine decarboxylase, inhibited both cadaverine and putrescine export. When cells were labeled with [3H]lysine, the great majority of the radioactivity recovered in exported polyamines was found in cadaverine. The cumulative data suggested that cadaverine formation may be caused by the action of intracellular ornithine decarboxylase upon lysine to produce cadaverine, which is then effluxed from the cell with a high degree of efficiency.
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PMID:Biosynthesis and selective export of 1,5-diaminopentane (cadaverine) in mycoplasma-free cultured mammalian cells. 812 59

A lipopolysaccharide (BP-LPS) isolated from killed Bordetella pertussis (Tohama strain) was determined to have low toxicity based on the mortality and decrease in body weight of BP-LPS-injected mice. BP-LPS, administered intradermally or intraperitoneally, clearly inhibited the growth of an MM46 murine mammary carcinoma. When compared with a toxic Escherichia coli-derived LPS, BP-LPS displayed excellent anti-tumour activity against MH134 hepatoma and Meth A fibrosarcoma. As part of a combined chemotherapy/immunotherapy regimen, BP-LPS also seemed to prolong the lifespan of mice inoculated with Lewis lung carcinoma. BP-LPS thus appears to have valuable characteristics as an anti-tumour agent.
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PMID:Anti-tumour activity of low-toxicity lipopolysaccharide of Bordetella pertussis. 819 67

Interleukin 8 (IL-8) is a recently described cytokine that functions as a potent neutrophil chemoattractant and activator. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) and the regulation of IL-8 gene expression to specifically test the hypothesis that ROI would induce production of IL-8 mRNA and protein. In lipopolysaccharide-stimulated human whole blood, the OH radical scavenger dimethyl sulfoxide (Me2SO) dramatically inhibited (approximately 90%) IL-8 production, but had minimal effects on the production of tumor necrosis factor, interleukin 1 beta (IL-1), and IL-6. To determine whether NADPH-oxidase-generated free radicals were critical in the regulation of IL-8, studies were performed using blood from patients with chronic granulomatous disease. In both normal individuals and patients with chronic granulomatous disease, production of IL-8 could be initiated with lipopolysaccharide, phytohemagglutinin, or aggregated immune complexes, and this production could be inhibited by Me2SO (1% v/v). To examine if oxidant stress represents a ubiquitous mechanism for the induction of IL-8, experiments were performed in cultured cell lines. In the human hepatoma cell line Hep-G2, Me2SO dose-dependently inhibited tumor necrosis factor-stimulated IL-8 production, with a 74 +/- 1% reduction observed at a Me2SO concentration of 1%. Direct exposure to ROI demonstrated that H2O2 stimulated IL-8 production in a dose-dependent manner in Hep-G2 cells, A549 pulmonary type II epithelial cells, and human skin fibroblasts; this induction could be prevented by addition of catalase. The production of IL-8 appeared to be specific to an oxidant stress since exposure of the cells to heat shock or chemical stress did not induce expression of IL-8. These studies demonstrate that oxidant stress is an important regulator of IL-8 gene expression and support the hypothesis that low levels of ROI may serve to initiate IL-8 production which then serves to recruit neutrophils to sites of inflammation.
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PMID:Regulation of interleukin 8 gene expression by oxidant stress. 824 94

alpha 1-Acid glycoprotein (AGP) is a major acute phase protein synthesized primarily by the liver. The AGP gene is transcriptionally activated in hepatocytes during the acute phase response to bacterial lipopolysaccharide. In this study, we analyzed an acute phase responsive element (APRE) located between nucleotide residues -127 to -104 relative to the transcription initiation site of the mouse AGP gene. Binding studies show that several trans-acting factors interact with the APRE. Using monospecific antibodies we demonstrate that three isoforms of the CCAAT/enhancer-binding protein (C/EBP) family, namely C/EBP alpha, C/EBP beta, and C/EBP delta, bind to the APRE. Furthermore, with liver nuclear protein from control animals, C/EPB alpha is the predominant form that binds to the APRE, whereas with nuclear proteins from acute phase-induced animals, C/EBP alpha is replaced by C/EBP beta. The mechanism of activation of the AGP gene during the acute phase response appears to involve an exchange of C/EBP alpha by C/EBP beta. C/EBP delta does not play a role in this reaction. Interestingly, the C/EBP binding site of the APRE partially overlaps a functional glucocorticoid responsive element. We present evidence that both purified C/EBP alpha and glucocorticoid receptor bind strongly to the APRE. By site-specific mutation, we have identified the C/EBP and glucocorticoid receptor binding sites in the APRE. These mutants were used in expression vectors to demonstrate that both C/EBP and glucocorticoid receptor are essential for maximal response to interleukin-6 and dexamethasone. These results demonstrate that the APRE is a composite binding site for multiple factors that are responsible for the transcriptional control of the mouse AGP. Finally, functional analyses indicate that C/EBP alpha, C/EBP beta, and C/EBP delta are strong transcriptional trans-activators of the AGP APRE in hepatoma cells. These data suggest that the regulatory activity of the C/EBP with the APRE in the liver may require interactions with adjacent proteins.
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PMID:trans-activation of the alpha 1-acid glycoprotein gene acute phase responsive element by multiple isoforms of C/EBP and glucocorticoid receptor. 834 Mar 93

Woodchuck (Marmota monax) hepatic cells, which were immortalized by the simian virus 40 large T antigen (SV40 Tag) produced nitric oxide (NO; measured as nitrite) in vitro from L-arginine (L-Arg) after lipopolysaccharide (LPS) treatment. NO synthesis was related to L-Arg and LPS concentration and plateaued at 1.0 mM L-Arg and 1.0 microgram/ml LPS. LPS-stimulated cells nitrosated morpholine to form N-nitrosomorpholine (NMOR) in the presence of L-Arg at pH 7.4. NMOR production increased 7-fold in LPS stimulated cells compared to unstimulated hepatocytes. N-nitrosodimethylamine (NDMA) was detected in the cell culture medium in the presence of LPS and L-Arg but without added dimethylamine. NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthase, inhibited formation of NO and NMOR, indicating that NO and nitrosating agents were formed via the L-Arg-nitric oxide pathway. These data are the first to report NO and N-nitrosamine production by immortalized hepatocytes and confirm earlier work showing that primary hepatocytes form NO in culture. This suggests that hepatic formation of N-nitroso compounds and/or NO could be an etiologic factor in hepatocellular carcinoma. Immortalized woodchuck hepatic cells may be useful as in vitro models to study the L-Arg-nitric oxide pathway and its possible role in liver carcinogenesis.
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PMID:Synthesis of nitric oxide and nitrosamine by immortalized woodchuck hepatocytes. 839 80

The concentration of plasma angiotensinogen increases upon induction of inflammation. Studies were carried out using serum samples collected from mice and rats after injection of lipopolysaccharide (LPS) to determine whether interleukin-6 (IL-6) is a mediator responsible for the inflammation-induced increase of angiotensinogen synthesis in liver cells. Serum collected from mice or rats 2 and 4 hr after injection of LPS contained a factor that stimulated [35S]methionine incorporation into angiotensinogen newly synthesized by rat hepatoma H4IIEC3 (H4) cells. Assay of IL-6 using an IL-6-dependent murine hybridoma, MH60.BSF2 cells, showed the presence of IL-6-like activity in sera of mice or rats 2 and 4 hr after injection of LPS. Anti-mouse IL-6 monoclonal antibody completely inhibited not only the IL-6-like activity present in LPS-treated mouse serum but also the ability of the serum to stimulate angiotensinogen synthesis of H4 cells. These results suggest that increased synthesis of angiotensinogen in the liver after induction of inflammation is mediated by IL-6, a cytokine important in immune reactions and the hepatic acute-phase response.
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PMID:Interleukin-6 as a mediator responsible for inflammation-induced increase in plasma angiotensinogen. 842 13

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