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)

When enriched large granular lymphocytes (LGLs) were activated by K562 cells substantial amounts of interleukin 1 (IL-1) could be detected in the supernatants as measured by the mouse thymocyte assay. IL-1 could also be produced by LGLs treated with other tumor cells according to their ability to be lysed by LGLs. Therefore PLC/PRF/5 hepatoma cells which were moderately sensitive to LGL attack stimulated moderate amounts of IL-1 from the LGLs. Yac-1 cells and human fibroblasts which are resistant to LGL cytolysis did not activate LGLs to produce significant amounts of IL-1. IL-1 was shown to be produced by LGLs and not by the stimulatory tumor cells. Interferon-alpha (IFN), which reduced the susceptibility of target cells to be lysed by LGLs, also inhibited their ability to stimulate IL-1 production from LGLs. The IL-1 stimulatory effect of tumor cells on LGLs could not be attributed to Mycoplasma or endotoxin contamination. It is suggested that LGLs release IL-1 when they encounter susceptible cells and that release of this cytokine is important in the subsequent lysis of target cells.
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PMID:Tumor cells stimulate interleukin 1 (IL-1) production from enriched large granular lymphocytes. 241 68

The monokine, cachectin/tumor necrosis factor (TNF) differs from interleukin 1 (IL-1) in primary structure and in recognition by a distinct cellular receptor. It does, however, encode effector functions that are similar to those of IL-1 and characteristic of the host response to inflammation or tissue injury. Accordingly, we examined the possibility that recombinant-generated human TNF regulates hepatic acute-phase gene expression. In picomolar concentrations, TNF mediated reversible, dose- and time-dependent increases in biosynthesis of complement proteins factor B and C3, alpha 1 antichymotrypsin, and decreases in biosynthesis of albumin and transferrin in human hepatoma cell lines (Hep G2, Hep 3B). Biosynthesis of complement proteins C2 and C4, and alpha 1 proteinase inhibitor were not affected by TNF. TNF also increased factor B gene expression, but had no effect on C2 gene expression, in murine fibroblasts transfected with cosmid DNA bearing the human C2 and factor B genes. The effect of TNF on acute-phase protein expression (C3, factor B, albumin) was pre-translational as shown by changes in specific messenger RNA content.
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PMID:Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. 242 91

The acute-phase response to inflammatory stimuli, characterized by increased synthesis of acute-phase proteins (APP), is often accompanied by changes in the glycosylation patterns of some of these proteins. While expression of APP genes in hepatocytes is regulated by monokines, mechanisms governing changes in glycosylation are not known. Exposure of human hepatoma cell line Hep 3B to conditioned medium from LPS-activated human monocytes and to medium from the keratocarcinoma cell line COLO-16 led to increased synthesis of alpha 1 proteinase-inhibitor and ceruloplasmin and to alterations of their glycosylation patterns similar to those seen in human serum in various inflammatory states. IL-1, tumor necrosis factor, and hepatocyte stimulating factor I increased synthesis of ceruloplasmin without alterations in the pattern of its glycosylation. These findings demonstrate that altered glycosylation seen in plasma in some inflammatory states can be explained by the effects of monokines on glycosylation in hepatocytes and that gene expression and glycosylation of some APP during the acute-phase response may be regulated by different mechanisms.
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PMID:Monokines regulate glycosylation of acute-phase proteins. 243 35

To assess the potential role of membrane interleukin 1 (mIL-1) in modulating expression of acute phase proteins, we studied the effect of fixed mouse peritoneal macrophages and isolated cell membranes on the synthesis of C3 and albumin in human hepatoma Hep 3B cells. An increase in C3 synthesis and decrease in albumin synthesis were detected after incubation of Hep 3B cells with fixed stimulated macrophages or with membrane preparations. Estimates of hepatocellular C3 and albumin mRNA indicated that the mIL-1 regulation was exerted at a pretranslational level. The changes in C3 and albumin expression induced by mIL-1 were inhibited by addition of anti-interleukin 1 (IL-1) antiserum to the macrophages, supporting the hypothesis that a form of IL-1 is present on the outer cell membrane of macrophages. Moreover, cell-surface iodination of macrophages allowed the detection of a 33-kDa IL-1 molecule, suggesting that an IL-1 species, similar to the intracellular precursor of IL-1 is present at the outer cell surface of macrophages. The expression of mIL-1 was temporally dissociated from IL-1 release, indicating that the cell-surface associated IL-1 activity is not the result of adsorbed soluble IL-1. These studies provide a basis for further investigation of the role of mIL-1 in modulating monocytes and macrophages function via cell-cell interactions.
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PMID:Macrophage membrane interleukin 1 regulates the expression of acute phase proteins in human hepatoma Hep 3B cells. 244 60

Human hepatoma (HepG2) cells respond to unfractionated conditioned media of human squamous carcinoma (COLO-16) cells and lipopolysaccharide-stimulated human peripheral blood monocytes by increasing the synthesis of alpha 1-acid glycoprotein, haptoglobin, complement C3, alpha 1-antichymotrypsin, alpha 1-antitrypsin, and fibrinogen, while decreasing the synthesis of albumin. The regulation of the acute phase proteins is mediated by hepatocyte-stimulating factors (HSF) and interleukin 1 (IL-1) present in the conditioned medium. Purified HSF-I from COLO-16 cells stimulates preferentially alpha 1-acid glycoprotein synthesis, whereas COLO-HSF-II stimulates preferentially the synthesis of haptoglobin, fibrinogen, and alpha 1-antitrypsin. HSF from monocytes, which has been identified as interferon-beta 2 (B cell stimulating factor-2), displayed the same activity as COLO-HSF-II. Dexamethasone alone had no effect on acute phase plasma protein synthesis but enhanced the response to various HSF severalfold. IL-1 had a relatively low stimulatory activity on the synthesis of alpha 1-acid glycoprotein, haptoglobin, and alpha 1-antichymotrypsin but strongly reduced the basal expression of fibrinogen. The only synergistic action between IL-1 and HSF (or interferon-beta 2) was noted for the synthesis of alpha 1-acid glycoprotein. Tumor necrosis factor active on other hepatic cells failed to modulate significantly the expression of any plasma proteins in HepG2 cells. These studies showed that for an optimal HepG2-cell response a combination of HSF (or interferon-beta 2), IL-1, and dexamethasone is needed. This finding might indicate the identity of some of those hormones involved in regulation of the hepatic acute phase response in vivo.
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PMID:Interaction among hepatocyte-stimulating factors, interleukin 1, and glucocorticoids for regulation of acute phase plasma proteins in human hepatoma (HepG2) cells. 244 59

Soluble serum beta 2-microglobulin has been thought to result from membrane shedding by activated T-lymphocytes. This hypothesis could explain the increase of beta 2-microglobulin serum levels during virally induced mononucleosis, but not elevated levels as observed in other virally induced and in malignant diseases. In this paper we demonstrate that beta 2-microglobulin is a true secretory protein, and that its synthesis in hepatocytes is modulated by IFNs but not by IL-1. While the 45,000 MW HLA antigen can be found only in cell lysates, beta 2-microglobulin is shown to be secreted also into the culture medium like other secretory proteins (e.g. albumin-factor B-complement C3). Furthermore, interferon alpha (IFN alpha) as well as interferon gamma (IFN gamma) directly stimulate, in a dose- and time-dependent manner, beta 2-microglobulin synthesis by human hepatoma cells (Mz-Hep-1 and PLC/PRF5) and murine hepatocyte primary cultures. The increase of beta 2-microglobulin production induced by interferons is demonstrated at both the protein and the RNA level, indicating that interferon acts at a pretranslational level. The interferon effect on beta 2-microglobulin synthesis is specific since synthesis of secretory proteins like complement C3 or albumin, and of a structural protein like actin, remains unchanged. In contrast to IFN, IL-1, the main mediator of acute phase response, does not change beta 2-M biosynthesis rate. These data indicate that (i) beta 2-microglobulin is a secretory protein, (ii) IFNs but not IL-1 can mediate increased beta 2-M serum levels, and (iii) the liver may be its primary source.
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PMID:Alpha- and gamma-interferon (IFN alpha, IFN gamma) but not interleukin-1 (IL-1) modulate synthesis and secretion of beta 2-microglobulin by hepatocytes. 245 38

Interleukin 6 (IL 6) and interleukin 1 (IL-1) regulate the expression of acute phase plasma proteins in rat and human hepatoma cells. Phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), partially mimics the stimulatory effect of IL-6 but reduces that effect of IL-1. TPA and IL-6 act synergistically. These regulatory properties of TPA are also manifested in HepG2 cells transiently transfected with an indicator gene construct carrying the IL-1/IL-6 regulatory enhancer element of the rat alpha 1-acid glycoprotein gene. IL-6 and IL-1 act independently of TPA-inducible kinase C, and of changes in intracellular Ca2+ concentrations. However, prolonged pretreatment of HepG2 cells with TPA results in a drastically reduced cytokine response that is proportional to the loss of cell surface binding activity for the cytokine. These data suggest that hormones activating protein kinase C probably play a contributing role in stimulating the expression of acute phase plasma protein genes but they may be crucial in controlling the responsiveness of liver cells to inflammatory cytokines during subsequent stages of the hepatic acute phase reaction.
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PMID:Phorbol ester modulates interleukin 6- and interleukin 1-regulated expression of acute phase plasma proteins in hepatoma cells. 246 Apr 62

The effects of various cytokines on synthesis and microheterogeneity of carbohydrate structure of alpha 1-proteinase inhibitor (PI) and alpha-fetoprotein (AFP) in the human hepatoma cell lines Hep 3B and Hep G2 were studied. In both lines, crude cytokine preparations from LPS-activated human monocytes (CM) and several cell lines led to increased PI and decreased AFP synthesis, while recombinant interleukin 1 (IL-1), recombinant tumor necrosis factor (TNF) and hepatocyte stimulating factor preparations (HSF) affected AFP but not PI production. Several of the crude cytokine preparations, but not IL-1, TNF, or HSF, caused Hep 3B cells to secrete forms of PI and AFP showing increased reactivity with Con A upon testing by affinity electrophoresis, while decreased reactivity with Con A was seen in these proteins secreted by Hep G2 cells. Determination of molecular size of PI inducing activity in CM showed a sharp peak at about 17 kD while AFP inhibiting activity was present in a very broad range of molecular size fractions maximal at 17-30 kD. Changes in patterns of glycosylation of these proteins were attributable to cytokines of about 30 kD in Hep 3B and 44 kD in Hep G2 cells. These findings demonstrate the existence of a family of glycosylation regulating cytokines, and suggest that distinct mechanisms within hepatocytes, responsive to different cytokines, may lead to increased or decreased Con A binding of glycoproteins and to altered gene expression.
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PMID:Effect of cytokines on glycosylation of acute phase proteins in human hepatoma cell lines. 246 70

The cytokine IFN beta 2/IL-6 has recently been shown to regulate the expression of genes encoding hepatic acute phase plasma proteins. INF beta 2/IL-6 has also been shown to be identical to MGI-2, a protein that induces differentiation of bone marrow precursor cells toward mature granulocytes and monocytes. Accordingly, we have examined the effect of IFN beta 2/IL-6 on expression of the IL-1- and tumor necrosis factor-unresponsive acute phase protein alpha 1-antitrypsin (alpha 1 AT) in human hepatoma-derived hepatocytes and in human mononuclear phagocytes. Purified human fibroblast and recombinant IFN beta 2/IL-6 each mediate a specific increase in steady-state levels of alpha 1 AT mRNA and a corresponding increase in net synthesis of alpha 1 AT in primary cultures of human peripheral blood monocytes as well as in HepG2 and Hep3B cells. Thus, the effect of IFN beta 2/IL-6 on alpha 1 AT gene expression in these cells is primarily due to an increase in accumulation of alpha 1 AT mRNA and can be distinguished from the direct, predominantly translational effect of bacterial lipopolysaccharide on expression of this gene in monocytes and macrophages. The results indicate that IFN beta 2/IL-6 regulates acute phase gene expression, specifically alpha 1 AT gene expression, in extrahepatic as well as hepatic cell types.
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PMID:Interferon beta 2/interleukin 6 modulates synthesis of alpha 1-antitrypsin in human mononuclear phagocytes and in human hepatoma cells. 247 25

A model system for studies of mechanisms governing the alterations of glycosylation of plasma glycoproteins was developed. The system employs two human hepatoma cell lines, Hep 3B and Hep G2, as target cells and agarose affinity electrophoresis with lectins for studies of microheterogeneity of alpha 1-protease inhibitor (PI), a model glycoprotein synthesized by hepatocytes. As an example for the application of the system, the effect of cytokines on major microheterogeneity of plasma proteins is demonstrated. The results indicate that interleukin 6, transforming growth factor beta 1 and, to some extent, tumor necrosis factor alpha are directly involved in regulating the pattern of glycosylation of plasma proteins in vitro, but the major effect is obtained by using combinations of interleukin 6, transforming growth factor beta 1, tumor necrosis factor alpha and interleukin 1. In addition, the results underline the dissociation between alteration of gene expression and the changes in the pattern of plasma protein glycosylation.
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PMID:Affinity electrophoresis for studies of mechanisms regulating glycosylation of plasma proteins. 248 77


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