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 small-complement C5 activation fragment, C5a, is a potent phlogistic molecule that, on binding to the C5a Receptor (C5aR), mediates contraction of smooth muscle, enhances vascular permeability, and promotes leukocyte functions such as directed chemotaxis, degranulation, mediator release, and production of superoxide anions. Although C5aR expression has traditionally been thought to be limited primarily to myeloid blood cells, including neutrophils, monocytes, macrophages, and eosinophils, we report here that C5aR is expressed by liver and lung cells as well as by cells in several other tissues. By Northern blot analysis, it was determined that mouse liver, baboon liver, human liver, and the human hepatoma-derived cell line HepG2 express a normal size (2.3 kb) C5aR mRNA; in HepG2 cells, the quantity of C5aR mRNA was comparable to that contained in dbcAMP-differentiated U937 cells. HepG2 cells were demonstrated to express the C5aR on their cell surface by flow cytometric and immunofluorescence analyses as well as by 125I-C5a binding assays. The binding data indicated that HepG2 cells express a single class of C5aR with a Kd of 1.18 nM and approximately 28,000 receptors per cell. In vivo expression of C5aR in human liver cells was demonstrated by in situ hybridization and immunohistochemistry analyses. Northern blot analysis of murine and baboon organs shows that, in addition to the liver, other tissues express C5aR mRNA in significant quantities, including the spleen, lung, heart, kidney, and intestine. Moreover, mice treated with LPS show a large increase in C5aR mRNA in all these tissues except the intestine. Immunostaining of human lung tissue demonstrated that bronchial and alveolar epithelial cells, as well as vascular smooth muscle and endothelial cells, also express the C5aR. Collectively, these data indicate that the C5aR is expressed in several different types of cells in liver and lung, and in yet undetermined cell types in spleen, heart, intestine, and kidney. Furthermore, these data suggest that the C5a anaphylatoxin mediates previously unrecognized functions by binding to tissue cells that express the C5aR.
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PMID:Cellular expression of the C5a anaphylatoxin receptor (C5aR): demonstration of C5aR on nonmyeloid cells of the liver and lung. 783 70

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

C-Reactive protein (CRP) is a minor acute phase reactant (APR) in the mouse, whereas CRP is the prototypical and one of the major positive APRs in all other mammals. MoCRP gene expression was tissue specific for the liver and induced by culture supernatants of LPS-activated macrophages. MoCRP gene expression by isolated hepatocytes in culture increased c, 3-fold in response to interleukin (IL)-1, but not IL-6. IL-6 is the most potent inflammatory cytokine for the induction of human CRP and many other APRs. By contrast, gene expression of the major APR of the mouse, serum amyloid P-component (SAP), a structural homologue of CRP, increased in response to either IL-1 or IL-6 under the same conditions. The region containing two potentially IL-1 responsive C/EBP elements in the moCRP gene failed to respond to IL-1 when a pCAT construct containing the elements was transfected into Hep 3B2 hepatoma cells. Therefore, IL-1 may influence the expression of the moCRP gene at the post-transcriptional rather than at the transcriptional level. The findings suggest that moCRP may be a minor APR because of the limited response of the gene to inflammatory cytokine signals.
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PMID:The mouse C-reactive protein (CRP) gene is expressed in response to IL-1 but not IL-6. 826 May 97

The low endotoxic lipid A derived from Porphyromonas gingivalis 381, 1-phospho beta(1-6)-linked glucosamine disaccharide with 3-hydroxy-15-methylhexadecanoyl and 3-hexadecanoyloxy-15-methylhexadecanoyl groups at the 2- and 2'-positions, respectively, induced mitogenic responses in LPS low responder C3H/HeJ as well as LPS responder C3H/HeN mouse splenocytes. The mitogenic activities of P. gingivalis lipid A in splenocytes of LPS responder mice were comparable to that of the synthetic Escherichia coli-type lipid A (compound 506). The addition of polymyxin B resulted in the inhibition of mitogenic activity. P. gingivalis lipid A also stimulated strongly nonspecific host resistance against Pseudomonas aeruginosa infection in BALB/c mice, and specific immune response in guinea pigs against infection with P. gingivalis. Furthermore, P. gingivalis lipid A demonstrated antitumour activity against MH134 hepatoma in C3H/HeN mice. These life-preserving with tumour regression properties were comparable to those of monophosphoryl lipid A derived from Salmonella minnesota Re 595. Thus, P. gingivalis lipid A appears to have beneficial properties as an immunopharmacological agent.
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PMID:Immunopharmacological activities of the nontoxic monophosphoryl lipid A of Porphyromonas gingivalis. 882 52

High level of fibrinogen in plasma is recognised as an important vascular risk factor. However, it is not known if the increase in fibrinogen is directly responsible for the vascular risk or is a marker of vascular inflammation. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since a parallel effect of cytokines on fibrinogen biosynthesis and on vascular injury was noted. Among the cytokines which induce the synthesis of fibrinogen, oncostatin M (OSM) is the most potent cytokine synthesised by activated monocytes for inducing fibrinogen synthesis by Hep G2 cells (human hepatoma cell line). Interestingly at the same concentrations needed for fibrinogen biosynthesis, OSM induces smooth muscle cell proliferation. In contrast, the cytokines IL-4, IL-10 and IL-13 which have a protective effect against vascular injury leading to atherosclerosis, dose dependently down regulate the biosynthesis of fibrinogen. This was due to both a decrease of IL-6 induced fibrinogen synthesis by hepatocytes, evidenced by a decrease in fibrinogen secretion in the medium and beta chain mRNA expression and to an inhibition of production of the hepatocyte-stimulating activity for fibrinogen biosynthesis (HSF) by LPS-activated monocytes. Noteworthingly, IL-10 induces a significant decrease of the production of OSM by LPS-activated monocytes. In situ activation of monocytes by cytokines in the vessel wall could also contribute to the deposition of fibrin(ogen) derivatives, identified as pathogenic factor.
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PMID:Regulation of fibrinogen biosynthesis by cytokines, consequences on the vascular risk. 897 38

Transferrin, as the major iron-transport protein in serum and other body fluids, has a central role in managing iron the body receives. Liver is a major site of transferrin synthesis, and in this study we present evidence that liver synthesis of human transferrin is suppressed by both the toxic metal lead and bacterial lipopolysaccharide, an inducer of the hepatic acute phase response. The responses of intact endogenous transferrin in the human hepatoma cell line HepG2 and chimeric human transferrin-chloramphenicol acetyltransferase genes in transgenic mice were examined. In HepG2 cells, 35S-transferrin protein synthesis and mRNA levels were suppressed by 100 microM and 10 microM lead acetate as early as 24 h after the initial treatment. Yet, synthesis of two proteins known to respond in the hepatic acute phase reaction, complement C3 and albumin, was not altered by the lead treatment. In transgenic mouse liver, lead suppressed expression of chimeric human transferrin genes at both the protein and mRNA levels, but LPS only suppressed at the protein level. The study indicates that lead suppresses human transferrin synthesis by a mechanism that differs from the hepatic acute phase response and that lead may also affect iron metabolism in humans by interfering with transferrin levels.
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PMID:A comparison of the suppression of human transferrin synthesis by lead and lipopolysaccharide. 907 50

We examined the antitumor effect of lipopolysaccharide extracted from Pantoea agglomerans, a Gram-negative bacterium, using intradermal administration on murine syngeneic tumors, Meth A fibrosarcoma, MH134 hepatoma and Lewis lung (LL) carcinoma. The latter two tumors are known to be relatively low in immunogenicity, highly metastatic and to have low sensitivity to biological response modifiers. Although the intradermal administration of LPSp had a significantly suppressive effect on the growth of all tumors, including seventy-five percent of complete regression of mice bearing Meth A tumor, no complete regression was observed in MH134 or LL tumors. In combination with cyclophosphamide given once prior to the administration of LPS, however, the antitumor effects by intradermal administration of LPS were significantly augmented and there was complete regression in all types of tumors. Pretreatment by anti-tumor necrosis factor antibody reduced the effect exerted by LPS, suggesting that induced tumor necrosis factor might have a crucial role. Toxicity of intradermal administration of LPS was 230-380 times less than that by the intravenous route. Thus clinical application of LPS administered intradermally in combination with chemotherapeutics such as cyclophosphamide appears promising in terms of its antitumor effect as well as toxicity.
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PMID:Anti-tumor effect of lipopolysaccharide by intradermal administration as a novel drug delivery system. 921 80

The results of the present study demonstrate that cells with the morphologic and phenotypic characteristics of blast cells that are obtained from the peripheral blood of patients with newly-diagnosed or recurrent acute myeloid leukemia (AML) can be stimulated by gamma interferon + lipopolysaccharide (IFN/LPS) to mediate in vitro cytolysis of an NK-insensitive hepatoma cell line. The conditions of IFN/LPS induction and subsequent assessment of cytotoxicity that were employed were identical to those used conventionally to test macrophage-mediated tumor cell cytotoxicity. What was totally unexpected was that these same blast cells, in the absence of stimulation with IFN/LPS, were also found to mediate high levels of spontaneous cytotoxicity against autologous bone marrow cells and against the U937 human promonocytic leukemia cell line in vitro. This high level of spontaneous cytotoxicity against autologous bone marrow or U937 promonocytic leukemia cells was not enhanced by IFN/LPS or MCSF under conditions that stimulated cytotoxic function in normal blood monocytes and was markedly reduced by pretreatment of the blast cells with IL2 under conditions that induced potent NK/LAK-mediated cytotoxicity. Neutralizing antibodies against TNFalpha and/or IL1alpha/beta eliminated the cytolytic function of blast cells against autologous bone marrow or U937 promonocytic leukemia targets. These findings demonstrate the existence of a population of cells with the morphologic characteristics of blast cells in the peripheral blood of AML patients which has the capacity to mediate spontaneous cytolysis of autologous bone marrow cells or a promonocytic leukemia cell line. These cells may be an immature variant of normal precursors produced as a consequence of the disordered hematopoietic environment in the marrow of AML patients. Alternatively, this function may be mediated by a subset of the leukemic blasts themselves.
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PMID:Cytolytic activity of peripheral blood blast cells from patients with acute myeloid leukemia. 947 27

Recent findings indicate that cytokine signaling can be modulated by other mediators of simultaneously activated signal transduction pathways. In this study we show that LPS and TNFalpha are potent inhibitors of IL-6-mediated STAT3 activation in human monocyte derived macrophages, rat liver macrophages and RAW 264.7 mouse macrophages but not in human hepatoma cells (HepG2) or in rat hepatocytes. Accordingly, LPS and TNFalpha were found to induce the expression of SOCS3 mRNA in each of the investigated type of macrophages but not in HepG2 cells. Using a specific inhibitor, evidence is presented that the p38 MAP kinase might be involved, especially for the inhibitory effect of TNFalpha.
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PMID:LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages. 1060 55

Endotoxemia leads to cytokine-mediated alterations of the hepatocellular sodium-taurocholate-cotransporting polypeptide (ntcp). We hypothesized that stimulated macrophages are essential transducers for down-regulating hepatocellular bile salt uptake in response to endotoxin (lipopolysaccharide [LPS]) exposure. Using an in vitro model, we exposed mouse macrophages (IC-21 cell line) to LPS for 24 hours. Concentrations of cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 increased 10.6-fold, 12.5-fold, and 444-fold, respectively, in LPS-conditioned IC-21 medium (CM) versus unconditioned IC-21 medium (UM). WIF-B rat hepatoma hybrid cells were incubated with either CM or UM or treated directly with medium containing recombinant TNF-alpha, IL-1beta, and IL-6. [(3)H]Taurocholate ([(3)H]TC) uptake decreased in WIF-B cells exposed to either TNF-alpha (54% of control), IL-1beta (78%), IL-6 (55%) as single additives, or in triple combination (TCC) (43%). A virtually identical decrease was observed after exposing WIF-B cells to CM (52%, P <.001). LPS had no direct effect on [(3)H]TC uptake. CM treatment did not decrease L-alanine transport in WIF-B cells. Blocking antibodies against TNF-alpha, IL-1beta, and IL-6 restored the diminished [(3)H]TC uptake in cells exposed to TCC and CM to 87% and 107% of controls, respectively. Northern blotting revealed that ntcp messenger RNA (mRNA) expression was significantly reduced in WIF-B cells after exposure to CM, and in primary rat hepatocytes exposed to CM or TNF-alpha (68%, 14%, and 29% of control, respectively). We conclude that macrophages and their ability to secrete the cytokines TNF-alpha, IL-1beta, and IL-6 may be essential in mediating the endotoxin-induced cholestatic effect of decreased hepatocellular bile salt uptake.
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PMID:Endotoxin-stimulated macrophages decrease bile acid uptake in WIF-B cells, a rat hepatoma hybrid cell line. 1061 37


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