UMLS:C0019204 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

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.
...
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

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.
...
PMID:Regulation of fibrinogen biosynthesis by cytokines, consequences on the vascular risk. 897 38

ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have examined the therapeutic effects of ONO-4007 on rat hepatocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 after tumor implantation of KMT-17 cells. ONO-4007 showed significant therapeutic effects on KDH-8 cells; by the administration of ONO-4007 (2.5 mg/kg) 70% of rats were cured and by the administration of ONO-4007 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatment prolonged the mean survival time of KDH-8-bearing rats. However, ONO-4007 had no effect on KMT-17 and SST-2 cells, and it had no direct effect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-a, those of IL-2, IL-4, IL-10 and interferon (IFN)-gamma were not induced. Using a bioassay, we found that the production of TNF-alpha in the tumor tissues was induced by ONO-4007 in a dose-dependent manner. KDH-8 cells were sensitive to human natural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resistant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.
...
PMID:A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. 921 14

We previously reported that the number of TNF-alpha-producing cells was increased in the liver of patients with type C chronic liver disease. To understand further the pathophysiology of this change, we examined serum levels of two soluble TNF receptors, TNF-alphaRI (p55) and -alphaRII (p75), and IL-10, all of which act as TNF-alpha buffer, and IL-15, a novel cytokine sharing many immunological activities with IL-2, using ELISA methods. We studied control individuals and patients with type C chronic liver disease, including asymptomatic hepatitis C virus (HCV) carriers with persistently normal serum ALT values, and those with chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Both types of sTNF-alphaR closely correlated with disease progression. Patients with LC and HCC had significantly elevated levels for sTNF-alphaRII compared with the other patient groups and controls. Serum IL-10 levels were significantly greater in all chronic liver disease groups than in controls. With respect to IL-15, the values were high in CH, LC and HCC compared with those of controls. Notably, HCC patients showed highest values for both IL-10 and IL-15, with significant differences from the other patient groups. Serial determinations revealed that interferon (IFN) treatment for CH patients resulted in the suppression of circulating IL-10 and IL-15 levels along with decrease in serum aminotransferase values. Both cytokines remained at decreased levels after cessation of therapy in patients who went into clinical and virological remission. On the other hand, treatment did not affect serum levels of sTNF-alphaRs. These findings indicate that serum levels of these molecules correlated with disease progress in chronic HCV infection, and that IL-10 and IL-15 may reflect the degree of inflammation in the liver. It is also suggested that both cytokines may be related to the development of HCC.
...
PMID:Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. 932 22

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.
...
PMID:HepG2 human hepatoma cells express multiple cytokine genes. 1008 37

We have shown that metastasis is suppressed by low-dose total-body irradiation (TBI) in tumor-bearing rats. We have evaluated the immunological effects of low-dose TBI. Total-body irradiation with 0.2 Gy was given 14 days after the implantation of 5 x 10(5) allogenic hepatoma cells (KDH-8) which produce transforming growth factor beta (TGF-beta). On day 21, the splenocytes and tumor-tissue infiltrating lymphocytes were analyzed by FACScan and RT-PCR for the mRNA of the genes that encode tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), TGF-beta, interleukin (IL)-4, IL-10 and IL-6. The same procedure was conducted with untreated rats and with rats that underwent local irradiation with 0.2 Gy. The low-dose TBI significantly decreased the incidence of lung and lymph node metastasis (P < 0.01), whereas the same dose of local irradiation had no effect on the incidence of metastasis. The proportion of CD8+ cells in splenocytes increased in the low-dose TBI group (P < 0.01) compared to the locally irradiated and the untreated groups. The tumor-tissue infiltrating lymphocytes were also significantly increased after low-dose TBI (P < 0.01). The FACScan analysis revealed that 72% of the tumor-tissue infiltrating lymphocytes were CD8+. In both spleen and tumor tissue after low-dose TBI, mRNA expression of the genes that encode IFN-gamma and TNF-alpha increased, while that of the Tgfb gene decreased. There was no expression of the mRNAs of the Il4, Il6 and Il10 genes. CD8+ cells and the cytokine network may play an important role in the antitumor effect of low-dose TBI.
...
PMID:The suppression of metastases and the change in host immune response after low-dose total-body irradiation in tumor-bearing rats. 1036 Jul 92

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. It is estimated that about 170 million people are chronically infected with HCV. Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma and HCV-related end-stage liver disease is, in many countries, the first cause of liver transplantation. HCV infection is characterized by its propensity to chronicity. Because of its high genetic variability, HCV has the capability to escape the immune response of the host. HCV is not directly cytopathic and liver lesions are mainly related to immune-mediated mechanisms, which are characterized by a predominant type 1 helper cell response. Co-factors influencing the outcome of the disease including age, gender and alcohol consumption are poorly understood and other factors such as immunologic and genetic factors may play an important role. Recent studies have shown that the combination therapy with alpha interferon and ribavirin induces a sustained virological response in about 40% of patients with chronic hepatitis C. The sustained response rates are mainly dependent on the viral genotype (roughly 60% in genotype non-1 and 30% in genotype 1). Reliable diagnostic tools are now available and useful for detecting HCV infection, to quantify viral load and to determine the viral type. The assessment of the viral quasispecies and the characterization of viral sequences might be clinically relevant but standardized and simple techniques are needed. The lack of animal models and of in vitro culture systems hampers the understanding of the pathogenesis of chronic hepatitis C and the development of new antivirals. New therapeutic schedules with higher and/or daily doses of alpha interferon do not seem to improve the efficacy greatly. The conjugation with polyethylene glycol (PEG) improved the pharmacodynamics and the efficacy of alpha interferon. Emerging new therapies include inhibitors of viral enzymes (protease, helicase and polymerase), cytokines (IL-12 and IL-10), antisense oligonucleotides and ribozymes. The first candidate compounds should be available in the next few years. The development of an effective vaccine remains the most difficult and pressing challenge. Because of the high protein variability of HCV, protective vaccines could be extremely difficult to produce and therapeutic vaccines seem more realistic. Considerable progress has been made in the field of HCV since its discovery 10 years ago but a major effort needs to be made in the next decade to control HCV-related liver disease.
...
PMID:Pathogenesis, diagnosis and management of hepatitis C. 1072 98

Helicobacter hepaticus has been reported to induce colitis, hepatitis, and hepatocellular carcinoma in several different murine models. The aim of this study was to determine if H. hepaticus will cause colitis in monoassociated mice lacking the interleukin-10 gene (IL-10(-/-) mice) and potentiate colitis in specific-pathogen-free (SPF) IL-10(-/-) mice. Germfree IL-10(-/-) mice on either a mixed (C57BL/6 x 129/Ola) or inbred (129/SvEv) genetic background were monoassociated with H. hepaticus ATCC 51448 by oral feeding and rectal enemas. In a second experiment, germfree IL-10(-/-) mice were colonized with stool from SPF mice that harbored or did not harbor endogenous H. hepaticus. After 7 to 9 weeks of colonization, weight loss and mortality were assessed, the colon was isolated for histology and IL-12 secretion, and mesenteric lymph node cells were assessed for T-cell activation markers. It was found that IL-10(-/-) mice monoassociated with H. hepaticus for up to 16 weeks showed almost no histologic colitis or increased IL-12 production. SPF IL-10-knockout mice had no significant difference in weight loss, mortality rate, histologic scores, colonic IL-12 secretion, or T-cell activation with or without H. hepaticus. We conclude that H. hepaticus does not induce or potentiate disease in our IL-10(-/-) mice and therefore is not required to induce colitis in genetically susceptible hosts.
...
PMID:Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. 1094 32

We analysed the regulation of G1-phase progression in relation to cytokine receptor signalling in HepG2 hepatoma cells, stably transduced with the IL-10 receptor after stimulation with Oncostatin M (OSM), IL-6, Leukaemia Inhibitory Factor (LIF) and IL-10. All cytokines induced STAT3 phosphorylation to approximately the same level, but only OSM, and to a lesser extent IL-6, induced STAT5 phosphorylation. The cytokines also stimulated phosphorylation of ERK in the order of decreasing effectiveness: OSM > IL-6 > LIF > IL-10. The same order of activity of the cytokines was observed on inhibition of DNA synthesis and accumulation of cells in the G1-phase of the cell cycle. These processes were accompanied by a decrease in cyclin A expression and CDK2 activity, and enhanced accumulation of p27kip1. The level of p27kip1 mRNA expression was unaffected by the cytokines, and maintenance of the elevated level of p27kip1 occurred independently of de novo protein synthesis. Furthermore, inhibition of proteasomal activity increased the level of p27kip1 in the unstimulated cells to the same level as in OSM-treated cells. Inhibition of MEK activation completely abrogated OSM and IL-6 induced p27kip1 accumulation, while expression of dominant negative STAT5 decreased the OSM and IL-6 mediated inhibition of DNA-synthesis and partially inhibited p27kip1 accumulation.
...
PMID:Oncostatin M and interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG2 cells. 1095 74

IL-10-related T cell-derived inducible factor (IL-TIF or IL-21) is a new cytokine structurally related to IL-10 and originally identified in the mouse as a gene induced by IL-9 in T cells and mast cells. Here, we report the cloning of the human IL-TIF cDNA, which shares 79% amino acid identity with mouse IL-TIF and 25% identity with human IL-10. Recombinant human IL-TIF was found to activate signal transducer and activator of transcription factors-1 and -3 in several hepatoma cell lines. IL-TIF stimulation of HepG2 human hepatoma cells up-regulated the production of acute phase reactants such as serum amyloid A, alpha1-antichymotrypsin, and haptoglobin. Although IL-10 and IL-TIF have distinct activities, antibodies directed against the beta chain of the IL-10 receptor blocked the induction of acute phase reactants by IL-TIF, indicating that this chain is a common component of the IL-10 and IL-TIF receptors. Similar acute phase reactant induction was observed in mouse liver upon IL-TIF injection, and IL-TIF expression was found to be rapidly increased after lipopolysaccharide (LPS) injection, suggesting that this cytokine contributes to the inflammatory response in vivo.
...
PMID:Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. 1095 42

1 2 3 4 5 6 7 8 9 10 Next >>