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)

Dendritic cells (DCs) are potent antigen-presenting cells that are capable of priming systemic antitumor immune response. Here, we evaluated the combined effectiveness of tumor lysate-pulsed DC immunization and interleukin (IL)-12 administration on the induction of antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. Mouse DCs were pulsed with lysate of BNL 1ME A.7R.1 (BNL), a BALB/c-derived HCC cell line, and then injected into syngeneic mice in combination with systemic administration of IL-12. Lymphocytes from mice treated with BNL lysate-pulsed DCs and IL-12 showed stronger cytolytic activity and produced higher amounts of IFN-gamma than those from mice treated with BNL lysate-pulsed DCs alone. Although immunization with BNL lysate-pulsed DCs alone did not lead to complete regression of established tumors, it significantly inhibited tumor growth compared with vehicle injection. Importantly, the combined therapy of BNL lysate-pulsed DCs and IL-12 resulted in tumor rejection or significant inhibition of tumor growth compared with mice treated with BNL lysate-pulsed DCs alone. In vivo lymphocyte depletion experiments demonstrated that this combination was dependent on both CD8+ and CD4+ T cells, but not natural killer cells. These results demonstrated that IL-12 administration enhanced the therapeutic effect of immunization of tumor lysate-pulsed DCs against HCC in mice. This combination of IL-12 and DCs may be useful for suppressing the growth of residual tumor after primary therapy of human HCC.
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PMID:Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma. 1160 95

Total RNA was extracted from murine hepatocytes, and the cDNA of interleukin 18(IL-18) was amplified by RT-PCR. The cDNA was introduced into the expression vector pJW2 and sequenced. Under heat induction, the recombinant murine IL-18(rmIL-18) was expressed in inclusion bodies in E. coli with the yield accounting for 18% of total bacteria proteins. The inclusion bodies were dissolved with 5 mol/L urea, and rmIL-18 was purified using Sephadex G-100 column chromatography. In the presence of 0.5 mg/L Con A, the purified rmIL-18 showed dose-dependent IFN-gamma-inducing activity in murine splenocytes. The purified rmIL-18 exhibited significant antitumor effects in Kunming mice challenged intraperitoneally (i.p.) with H22 hepatocarcinoma when administered 10 micrograms rmIL-18 i.p. on days 1, 4 after challenge, and the mice survived resisted the rechallenged with H22 cells.
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PMID:[Expression and purification of murine interleukin 18 in Escherichia coli and its antitumor effects]. 1179 19

STAT transcription factors signal from the plasma membrane to the nucleus in response to growth factors and cytokines. We have investigated whether plasma membrane "rafts" are involved in cytokine-activated STAT signaling. Cytokine-free human hepatoma Hep3B cells or cells treated with interleukin-6 (IL-6) or orthovanadate (a general activator of STATs) were fractionated, and plasma membrane raft fractions were obtained by equilibrium sedimentation or flotation through discontinuous sucrose gradients using either non-detergent or detergent-based (saponin or Triton X-100) methods. By Western blotting the plasma membrane raft fractions obtained using either non-detergent or detergent-based methods contained significant amounts of STAT1 and STAT3 (up to approximately 10% of the total cytoplasmic amount) as well as the integral raft proteins caveolin-1 and flotillin-1, the IL-6-receptor signal transducing chain gp130, the interferon-gamma receptor alpha chain (IFN-gammaRalpha), and the chaperone glucose-regulated protein 58 (GRP58/ER-60/ERp57). Upon activation of signaling by IL-6 or orthovanadate the respective Tyr-phosphorylated STAT species were now also observed in the membrane raft fraction but in a form deficient in DNA binding. The data show pre-association of STATs with plasma membrane rafts in flotation fractions, which also contained caveolin-1 and flotillin-1, and suggest that Tyr phosphorylation may not in itself be sufficient to cause the departure of PY-STATs from plasma membrane rafts. Methyl-beta-cyclodextrin, which sequesters cholesterol and disrupts plasma membrane rafts, markedly inhibited IL-6- and IFN-gamma-induced STAT signaling. Signaling through specialized raft microdomains may be a general mechanism operating at the level of the plasma membrane through which cytokines and growth factors activate STAT species (the "raft-STAT signaling hypothesis").
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PMID:Cytokine signaling: STATS in plasma membrane rafts. 1181 25

The 155-kd soluble complement regulator factor H (FH), which consists of 20 short consensus repeats, increases the affinity of complement factor I (FI) for C3b by about 15 times. In addition to its cofactor activity, it prevents factor B from binding to C3b and promotes the dissociation of the C3bBb complex. The primary site of synthesis of FH, as well as of FI, is the liver, but the cell types responsible for the hepatic synthesis of both factors have not yet been clearly identified. In contrast to FI-mRNA, which was detectable only in hepatocytes (HC), FH-specific mRNA was identified in both HC and Kupffer cells (KC). As calculated for equal amounts of mRNA isolated from both cell types, FH-specific mRNA was found to be nearly 10-fold higher in KC than in HC, leading to the conclusion that KC are an abundant source of FH. Of the investigated proinflammatory cytokines IL-6, TNF-alpha, IL-1beta, and IFN-gamma, only IFN-gamma up-regulated FH-specific mRNA up to 6-fold in both primary HC and KC. This was also demonstrable on the protein level. However, FH-specific mRNA was not inducible in the rat hepatoma cell line H4IIE, which did not express FH-specific mRNA and could not be up-regulated in FAO cells that constitutively expressed FH-specific mRNA. This demonstrates that transformed cell lines do not reflect FH regulation in isolated primary HC. In addition to IFN-gamma, the endotoxin lipopolysaccharide (LPS) up-regulated FH-specific mRNA nearly 10-fold in KC after stimulation at concentrations of 10 or 1 ng/ml. In contrast, concentrations of up to 2 microg LPS/ml did not show any effect on HC. Our data suggest that LPS does not regulate the expression of FH in HC.
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PMID:Constitutive expression and regulation of rat complement factor H in primary cultures of hepatocytes, Kupffer cells, and two hepatoma cell lines. 1185 May 31

Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All treatments known so far rely on the antiviral activity of interferon alfa (IFN-alpha) that is given alone or in combination with ribavirin. Unfortunately, only a fraction of the patients clear the virus during therapy and for those who do not respond there is currently no alternative treatment. Selectable subgenomic HCV RNAs (replicons) have been recently used to investigate the effect of IFN-alpha on HCV replication. However, it has not yet been analyzed whether other cytokines also play a role in the innate immune response against HCV. Here we show that IFN-gamma inhibits protein synthesis and RNA replication of subgenomic and genomic HCV replicons. We further show that the inhibitory action of IFN-gamma does not rely on the production of nitric oxide or the depletion of tryptophan. In conclusion, our results suggest that cytotoxic T cells and natural killer cells may contribute to HCV clearance not only by cell killing but also by producing IFN-gamma, thereby enhancing the intracellular inhibition of viral replication.
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PMID:Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. 1187 Mar 86

A direct comparison of the inhibitory effects of alpha, beta, and gamma interferons (IFNs) on replication of a hepatitis C virus subgenomic replicon in a hepatoma cell line revealed similarities in antiviral potency. However, alternate IFN-induced antiviral mechanisms were suggested following observations of striking differences between IFN-gamma and IFN-alpha/beta with respect to strength and durability of the antiviral response and the magnitude and pattern of IFN-mediated gene expression.
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PMID:Comparative analysis of anti-hepatitis C virus activity and gene expression mediated by alpha, beta, and gamma interferons. 1236 59

Patients with hepatitis C virus (HCV) related-liver cirrhosis (LC) often develop hepatoma. The type 1 helper T cell (Th1) response presents an antitumor effect. We evaluated the Th1 response in patients with HCV-related LC at the single-cell level and examined the influence of transforming growth factor (TGF)-beta, an immunosuppressive cytokine, on the Th1 response. We determined the ratios of Th1-type cytokine (IFN-gamma, IL-2)-producing cells to CD3-positive cells in 14 patients (LC group) and in 16 normal controls using flow cytometry and measured serum TGF-beta(1) and TGF-beta(2) levels by ELISA. We then incubated, peripheral blood mononuclear cells from seven healthy volunteers with recombinant TGF-beta(1) or TGF-beta(2) for 48 h, and determined the ratio of IFN-gamma producing cells to CD3-positive cells. The IFN-gamma ratio was significantly lower in the LC group (29.7+/-0.3 vs. 44.2+/-15.0%, P<0.01). The serum TGF-beta(2) level was significantly increased in the LC group (601+/-232 vs. 329+/-118 pg/ml, P<0.001). TGF-beta(2) significantly suppressed IFN-gamma production at the single-cell level (10.0+/-4.3 vs. 7.3+/-2.0%, P<0.05). These findings indicated that the enhanced down-regulation of Th1 by TGF-beta(2) in patients with HCV-related LC might be effective against hepatoma.
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PMID:Th1 down-regulation at the single-lymphocyte level in HCV-related liver cirrhosis and the effect of TGF-beta on Th1 response: possible implications for the development of hepatoma. 1239 30

The HBx-derived, HLA-A2.1 restricted peptides, XEP-3, XEP-4, and XEP-6, induced activation of specific CTLs from patients with HBV in vitro. XEP-6 peptide induced the strongest response among the three peptides in CTLs from the blood samples of patients that were HBsAg positive. It was not clear whether the stage of disease (chronic infection, cirrhosis or hepatoma) was related to the responsiveness of the CTLs to each peptide. We vaccinated HLA-A2/K(b) transgenic mice with these peptides encapsulated in pH-sensitive liposomes at various concentrations and tested their ability to protect against challenge with rVV-HBx. Mice immunized with encapsulated peptides were protected against viral challenge whereas those immunized with empty liposomes were not. In general, 5 micro g of each peptide per head inoculation was sufficient to give protection after 2 weeks. After 3 weeks, this protective effect was increased. This effect of time was more important on the level of protection than the initial dose of the peptide. To explain the protective effect, IFN-gamma secreting CD8(+) cells isolated from mice 3 weeks after immunization were analyzed ex vivo. There was little dose dependency of peptide on IFN-gamma secretion except for XEP-3. The variations in the results may reflect the chemical properties of the peptides, such as solubility and binding affinity. In conclusion, epitope peptides derived from HBx can induce specific CTL activation and lead to cellular immunity in vitro and in vivo by inducing the peptide-specific CD8(+) CTLs. Thus, pH-sensitive liposomes increase the immune response following immunization with a peptide vaccine. This could be used for the treatment of HBV-related disease.
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PMID:HLA-A2 1 restricted peptides from the HBx antigen induce specific CTL responses in vitro and in vivo. 1239 8

Various cytokines and chemokines play a role in carcinogenesis. However, no study has previously been undertaken to investigate comprehensively the expressions of cytokines and chemokines in hepatoma cells. In this study, we determined which cytokines and chemokines are expressed in hepatoma cells. Recently, it was reported that the expressions of several chemokines could be increased by Fas stimulus in many normal and cancer cells. Therefore, we also investigated whether chemokines expression is regulated by Fas ligation. To address this issue, we performed RNase protection assays upon 13 cytokines and 8 chemokines genes in 10 human hepatoma cell lines, comprising 8 hepatitis B virus (HBV)-associated hepatoma cell lines. Transforming growth factor-beta2 (TGF-beta2) was found to be expressed in 8 HBV-associated hepatoma cell lines, and to be potently expressed in 5 cell lines; however, the mRNA expressions of interleukin-10 (IL-10), IL-12, interferon-gamma(IFN-gamma) and tumor necrosis factor-alpha(TNF-alpha) were not detected in any cell lines examined. Among the chemokines investigated in this study, IL-8 was expressed by 8 HBV- associated hepatoma cell lines, and monocyte chemoattractant protein-1 (MCP-1) by 7 HBV-associated hepatoma cell lines. However, the mRNA expressions of macrophage inflammatory protein-1alpha(MIP-1alpha), MIP-1beta, interferon-inducible protein-10 (IP-10), RANTES, lymphotactin and I-309 were either very weak or undetectable. Fas ligation did not increase chemokines expression in hepatoma cells. Conclusively, TGF-beta2, IL-8 and MCP-1 were overexpressed in HBV-associated hepatoma cells, and the expressions of chemokines were not increased by Fas ligation in human hepatoma cells.
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PMID:Expression patterns of cytokines and chemokines genes in human hepatoma cells. 1240 81

EB virus vector pEBAF, which contains human alpha-fetoprotein gene promoter and enhancer was used as expression vector. Two recombinant expression vectors, pEBAF/P35 and pEBAF/P40, were constructed and co-transfected into 4 cell lines. RT-PCR suggested that both P35 and P40 mRNA are expressed in HepG2 cell secreting alpha-fetoprotein, in contrast, neither P35 mRNA nor P40m RNA was expressed in non-secreting alpha-fetoprotein cell lines. This proved that the pEBAF may lead to target--expression of IL-12 in hepatoma and has tissue specificity and exclusiveness for hepatoma. The cotransfected Hyg resistant clone of HepG2 cell was selected. Northern blot indicated that the HepG2 cell clone had transcription of P35 mRNA and P40 mRNA. Expression of IL-12 in the supernatant of HepG2 cell culture had been testified by ELISA and Western blot. IL-12 biological activity test indicated that the expressed IL-12 had activity of inducing IFN-gamma production. This research laid the foundation to develop an in vivo gene therapy strategy pointing to the treatment of hepatocellular carcinoma, with selective killing of the tumor cells and no effect on the normal hepatic cells.
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PMID:[The target--gene expression of interleukin--12 in HepG2 cells]. 1252 39


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