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)

In rat hepatoma H-35 cells, TNF-alpha, like IL-1 beta, stimulates the synthesis and secretion of type 1 acute phase plasma proteins, including alpha 1-acid glycoprotein (AGP), complement component 3 (C3), hemopexin, and haptoglobin. TNF and IL-1 in combination act additively to synergistically on the expression of AGP and C3 but not on hemopexin and haptoglobin. The cytokine stimulation of AGP and C3 genes is further enhanced by hepatocyte growth factor. The effect of TNF is mediated by the type I TNF receptor as judged from the TNF-like effect elicited by the agonist antibodies to type I but not type II TNF receptor. The data suggest that, although TNF and IL-1 share considerable overlap in their signal transduction mechanism, cytokine-specific signal pathways exist that affect a subset of acute phase plasma protein genes. A potential regulatory role is attributed to the transcription factors C/EBP beta and NF-kB based on studies on transiently transfected H-35 cells.
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PMID:TNF-alpha, IL-1 beta, and hepatocyte growth factor cooperate in stimulating specific acute phase plasma protein genes in rat hepatoma cells. 769 42

The synthesis of some class 1 acute-phase proteins (APP), including C-reactive protein (CRP) and serum amyloid A (SAA) protein is completely blocked by the IL-1 receptor antagonist (IL-1Ra), whereas the production of fibrinogen, a class 2 APP, is increased by IL-1Ra in hepatoma cells, but this has never been tested in human hepatocytes in primary culture. Since previous studies on the contributions of cytokine inhibitors in connective tissues diseases suggested that IL-1 and tumour necrosis factor-alpha (TNF-alpha) might play an important role in the regulation of CRP, we decided to examine in more detail the respective roles of IL-1 beta, IL-6, and TNF-alpha and their inhibitors in the production of APP by human primary hepatocytes versus the hepatoma cell line PLC/PRF/5. In the hepatoma cell line, IL-1 beta and/or TNF-alpha had synergistic effects with IL-6 on the production of CRP and SAA. In contrast, these cytokines were devoid of effect in normal hepatocytes. The production of fibrinogen was increased by IL-6 and decreased by IL-1 (and TNF-alpha) in both cell types. The secretion of CRP and SAA by primary hepatocytes incubated with a cytokine-rich mononuclear cell-conditioned medium was totally unaffected by IL-1Ra or anti-TNF-alpha antibodies. In contrast, the addition of IL-1Ra increased the production of fibrinogen by both hepatoma cells and primary hepatocytes incubated with the mononuclear cell-conditioned medium. We therefore conclude that IL-1 beta and TNF-alpha do not exert any significant effect on the synthesis of CRP and SAA by human primary hepatocytes.
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PMID:IL-1 receptor antagonist (IL-1Ra) does not inhibit the production of C-reactive protein or serum amyloid A protein by human primary hepatocytes. Differential regulation in normal and tumour cells. 774 70

The in vitro expression level of interleukin-8 (IL-8) correlates with the metastatic potential of human melanoma cells. The purpose of this study was to determine whether the expression level of IL-8 in human melanoma cells is influenced by the organ microenvironment. A375P cells, a low metastatic human melanoma, and A375SM cells, a highly metastatic variant, were injected into the subcutis (s.c.), spleen (to produce liver metastases), and lateral tail vein (to produce lung metastases) of athymic nude mice. Northern blot and immunohistochemical analyses determined that s.c. tumors, lung lesions, and liver lesions expressed high, intermediate, and low IL-8, mRNA, and protein, respectively. This differential regulation of IL-8 was not due to the size or density of the lesions or to selection of subpopulations of cells. We based this conclusion on the results of three experiments: (a) melanoma cell lines established in culture from in vivo-growing tumors exhibited similar levels of IL-8 mRNA transcripts; (b) in a crossover experiment, the level of IL-8 mRNA was always high in A375 tumors reestablished in the skin and low in the tumors reestablished in the liver, regardless of whether the melanoma cells had been first harvested from s.c. or liver tumors; and (c) A375 melanoma cells cocultured with human keratinocytes produced high levels of IL-8 protein, whereas A375 cells cocultured with highly differentiated human hepatoma cells produced decreased levels. When A375P cells were then incubated with cytokines associated with keratinocytes (IL-1 and interferon beta) or hepatocytes (transforming growth factor alpha or beta), IL-1 enhanced the production of IL-8 protein, whereas TGF-beta decreased its production. These data show that IL-8 expression in melanoma cells is modulated by local host factors.
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PMID:Regulation of interleukin-8 expression in human melanoma cells by the organ environment. 775 1

The presence of positive acute phase proteins within the circulation of rheumatoid arthritis patients suggests that elevated cytokine production associated with this chronic inflammatory disorder initiates the hepatic acute phase response. Cytokines produced at inflammatory lesions are believed to travel via the circulation to the liver where they induce acute phase protein production by hepatocytes. To test whether serum from rheumatoid arthritis patients contained sufficient levels of cytokines to promote an acute phase response in vitro, a bioassay was developed that employed the human hepatoma cell line Hep3B. These cells produced the acute phase protein serum amyloid A (SAA) in response to a combination of recombinant IL-1 beta and IL-6 or to monocyte conditioned medium. Serum (or plasma) from normal individuals or from rheumatoid arthritis patients did not induce SAA production by Hep3B cells. Moreover, these serum samples did not prevent SAA production induced by monocyte conditioned medium, indicating that they did not contain inhibitors of cytokine activity. Despite the inactivity of serum samples, synovial fluid samples obtained from rheumatoid arthritis patients were active in the hepatocyte bioassay and promoted SAA synthesis. One synovial fluid sample was analysed in detail to identify cytokines responsible for the SAA-inducing activity. Neutralizing antisera against IL-6 and IL-1 beta blocked this activity by > 90% whereas anti-IL1 alpha and anti-TNF-alpha sera were without effect. Absolute cytokine levels within the synovial fluid sample were determined by ELISA; IL-6, IL-beta and TNF-alpha, but not IL-1 alpha, were confirmed to be present. Moreover, the synovial fluid sample contained a large amount of the IL-1 receptor antagonist. These data indicate, therefore, that synovial fluid recovered from an inflamed joint contains all the necessary cytokines in balance with inhibitors to promote SAA production by Hep3B cells. The steady state levels of these factors within the plasma compartment, however, were insufficient to induce the acute phase response by cultured Hep3B cells, suggesting that this system does not mimic the relationship between the circulation and the liver that likely exists in rheumatoid arthritis patients.
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PMID:Synovial fluid from rheumatoid arthritis patients contains sufficient levels of IL-1 beta and IL-6 to promote production of serum amyloid A by Hep3B cells. 778 41

Serum amyloid A (SAA) protein is a major acute phase reactant in human and many other species. Infections and traumatic inflammation are characterized by a rapid increase of SAA; its concentration in the plasma may augment many-fold. Cytokines such as IL-1 and IL-6 are considered mediators of acute phase protein synthesis. The most accredited mechanism of action of IL-1 in inflammatory diseases is the stimulation of PGE2 release, which is highly dependent on the concentration of IL-1. In this study we found that human Hep 3B hepatoma cells treated with the combination of hrIL-6 (10ng/ml) plus hrIL-1 (1ng/ml) produced an augmentation in steady-state levels of SAA mRNA (87%) compared to hrIL-6 (10ng/ml) plus PGE2 (5 microM), which induced an increase of only 33%, compared to IL-6 alone, while cells treated with hrIL-6 plus PGE2 (0.5 microM) had a similar effect as hrIL-6 did alone. Moreover, the addition of exogenous PGE2 (5 microM) to the cell cultures produced no significant increase in concentration of SAA mRNA compared to the control. In addition, according to the data obtained by the blot analysis we also found, by ELISA method, that hrIL-6 acts in synergism with hrIL-1 on SAA protein secretion in human Hep 3B hepatoma cell cultures after 48 h incubation. In fact, the cell cultures treated with hrIL-6 plus hrIL-1 caused a higher release approximately 1.5-4-fold of SAA protein than the cells treated with IL-6 plus PGE2 5 microM or IL-1 + PGE2 5 microM, respectively. The synergistic effect of hrIL-6 plus hrIL-1 beta was inhibited by hrIL-1 receptor antagonist (hrIL-1ra) 50 micrograms/ml, a protein which specifically binds to the IL-1 receptor and is structurally similar to IL-1 beta but with no IL-1-like activity; while indomethacin (5 microM) was ineffective. These results strongly suggest that the synergism between hrIL-6 plus hrIL-1 on the transcription and the protein release of SAA release is not due to a PGE2-dependent process in human Hep 3B hepatoma cells. This finding highlights a specific biological effect of IL-1 not in relation to PGE2, suggesting a specific mechanism of action for IL-1 in regulating acute phase protein synthesis.
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PMID:Synergistic activation of serum amyloid A (SAA) by IL-6 and IL-1 in combination on human Hep 3B hepatoma cell line. Role of PGE2 and IL-1 receptor antagonist. 779 46

Lipopolysaccharide (LPS)-binding protein (LBP) has been reported to be an acute-phase protein. LBP binds to LPS with a high affinity; LPS-LBP complexes then interact with the receptor CD14, resulting in increased expression of LPS-inducible genes. Hepatocytes represent a major source of LBP, but little is known about the regulation of rodent hepatocyte LBP synthesis. In these studies, undertaken to characterize hepatocyte LBP expression, we show that greater-than-20-fold increases in LBP mRNA levels in hepatocytes occurred following injection of LPS or turpentine in rats. In primary cultures of rat hepatocytes, the addition of interleukin-6 (IL-6) and LPS led to 4.5- and 3.2-fold stimulation in LBP mRNA levels, respectively. The induction of LBP by IL-6 or LPS was attenuated by dexamethasone. In contrast to IL-6 and LPS, in the presence of 10(-6) M dexamethasone, IL-1 and tumor necrosis factor (TNF) led to maximal LBP mRNA induction levels, 4.7- and 3.8-fold, respectively, suggesting that IL-6 and LPS stimulate LBP expression by mechanisms different from those of IL-1 and TNF. Similar induction levels of LBP mRNA were seen in rat H35 hepatoma cells for all four stimuli, and dexamethasone inhibited these responses. Dexamethasone alone increased the spontaneous induction in primary hepatocytes at early time points but suppressed induction at later time points. Furthermore, hepatocytes from rats treated with LPS in vivo exhibited a > 10-fold increase in mRNA expression in response to LPS and enhanced responses to TNF and IL-1. As with the normal hepatocytes, dexamethasone inhibited the LPS-dependent induction in the LPS-treated rat hepatocytes. These data suggest that LBP synthesis by hepatocytes is under the control of LPS, IL-1, TNF, IL-6, and glucocorticoids and that the LPS treatment primes hepatocytes for subsequent responses to LPS, TNF, and IL-1 for LBP synthesis.
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PMID:Role of lipopolysaccharide (LPS), interleukin-1, interleukin-6, tumor necrosis factor, and dexamethasone in regulation of LPS-binding protein expression in normal hepatocytes and hepatocytes from LPS-treated rats. 779 54

Previous studies of murine serum amyloid A (SAA) regulation during inflammatory states or following exposure to macrophage-conditioned medium have raised the possibility that both post-transcriptional and transcriptional mechanisms participate in induction of this family of proteins. Since IL-6 and IL-1 have been shown to induce SAA in human hepatoma cell lines, we explored the possibility that these cytokines might induce human SAA through post-transcriptional as well as transcriptional mechanisms. In kinetic studies, we found that continuous exposure of Hep 3B cells to either IL-6 or IL-1 beta alone caused only minimal increases in SAA mRNA and marginal increases in transcription (as measured by nuclear runon). In contrast, the combination of these cytokines led to a 23-fold increase in transcription, maximal at 12 h, with continuing increase in mRNA, achieving levels more than 1,000-fold greater than baseline by 72 h. This massive disparity between increases in mRNA and in transcription rate strongly supports the participation of post-transcriptional mechanisms in SAA induction by (IL-6 + IL-1 beta), whereas the lag between peaks of transcription and mRNA abundance reflects a relatively slow degradation rate of SAA mRNA. As observed by other workers, mean size of SAA mRNA decreased progressively over the course of incubation. Simultaneous kinetic studies of complement factors B and C3, haptoglobin, and alpha-1 protease inhibitor revealed several different patterns of response to IL-6 and IL-1 beta.
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PMID:Induction of human serum amyloid A in Hep 3B cells by IL-6 and IL-1 beta involves both transcriptional and post-transcriptional mechanisms. 781 86

Transferrin (Tf) plays an important role during immunologic activation by donating iron to activated lymphocytes. Therefore, synthesis by lymphomyeloid cells has been investigated. Mouse macrophages and macrophage cell lines synthesized Tf, with levels being markedly increased by gamma-interferon (gamma-IFN) and, to a lesser extent, by interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF alpha). Tf was also produced by phytohemagglutinin-stimulated human T cells and two T-cell lines and was increased by IL-2. Even after appropriate activation, none was synthesized by human macrophages or monocytic cell lines or by mouse T cells, T-cell lines, or thymus cells. In both species, B-lineage cell lines were negative. Tf was also synthesised by macrophages from congenitally hypotransferrinemic mice and was responsive to gamma-IFN, but levels were lower than those from normal controls. Synthesis by human and murine hepatoma cells was increased by IL-6 but unaffected by IL-1, TNF alpha, or gamma-IFN. Iron decreased synthesis by hepatoma cells but had no effect on the lymphomyeloid cells. Tf mRNA levels paralleled protein synthesis, suggesting that regulation was pre-translational. Thus, Tf synthesis by lymphomyeloid cells is regulated differently from hepatic synthesis, which is consistent with the suggestion that Tf may act in a paracrine (mouse) or autocrine (human) manner on activated lymphocytes.
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PMID:Cytokine-mediated regulation of transferrin synthesis in mouse macrophages and human T lymphocytes. 784 92

The effects of interferon-gamma (IFN-gamma), alone and in combination with IL-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha), on in vitro erythropoietin (Epo) production by the human hepatoma Hep3B cell line were evaluated. The addition of IFN-gamma to either unstimulated or cobalt chloride (CoCl2)-treated Hep3B cells resulted in a dose-dependent inhibition of Epo release in the medium by as much as 70% at 1000 U/ml. Half-maximal inhibition was observed at around 50 U/ml. According to previous observations, IL-6 had a stimulatory effect on Epo production by CoCl2-treated Hep3B cells; however, the simultaneous addition of IFN-gamma and IL-6 resulted in a reversal of the stimulatory effects due to IL-6. IFN-gamma and IL-1 had an additive inhibitory effect, whereas IFN-gamma and TNF-alpha acted in a synergistic fashion in inhibiting Epo production by Hep3B cells. The inhibitory effect of IFN-gamma appeared to be due to a down-modulation of Epo mRNA levels in CoCl2-treated Hep3B cells, as shown by Northern blot analysis. These data indicate that Epo production by hepatoma cells in vitro is inhibited by IFN-gamma, and that a complex network of interacting cytokines may regulate Epo production in response to an hypoxic stimulus. Overall, these results also suggest that IFN-gamma might have a role in the defective Epo production observed in several inflammatory and immunemediated disorders characterized by relatively high IFN-gamma plasma levels.
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PMID:Inhibition of erythropoietin production in vitro by human interferon gamma. 794 42

The liver plays a central role in the systemic acute phase response of an organism to injury. Plasminogen activator inhibitor-1 (PAI-1), a major regulator of fibrinolysis, is an important component of the acute phase response in humans. The source of plasma PAI-1 has been a matter of controversy, but recent in situ hybridization experiments have demonstrated that human hepatocytes express the PAI-1 gene in vivo. However, little is known about regulation of human hepatic PAI-1 gene expression by mediators of the acute phase response. We have analyzed the regulation of PAI-1 mRNA accumulation by interleukin (IL)-1, IL-6, and dexamethasone, known mediators of the acute phase response, in HepG2 cells, a highly differentiated human hepatoma cell line that produces a broad spectrum of acute phase proteins including PAI-1. Incubation of HepG2 cells with IL-1 resulted in a rapid and transient 40-fold induction of the 3.2-kilobase PAI-1 mRNA and a 30-fold induction of the 2.2-kilobase PAI-1 mRNA. Although IL-6 alone had only a modest effect on PAI-1 expression, in combination with IL-1, it caused a synergistic induction of PAI-1 mRNA accumulation. Dexamethasone alone did not increase PAI-1 mRNA accumulation but enhanced it in combination with IL-1. Using nuclear run-on experiments, we determined that the mechanism by which IL-1 alone, or in combination with IL-6, induced PAI-1 mRNA accumulation was to cause a 10-15-fold, transient stimulation of PAI-1 gene transcription. We found no evidence of an effect of these cytokines on PAI-1 mRNA stability. These data demonstrate that mediators of the acute phase response induce the accumulation of PAI-1 mRNA in human hepatoma cells by rapidly and transiently increasing the transcription of the PAI-1 gene.
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PMID:Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response. 803 68

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