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)

Hypoxia-induced erythropoietin (Epo) production in vitro is suppressed by interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF) and phorbol esters. Herein, the Epo-synthesizing human hepatoma cell line HepG2 was used to investigate whether protein kinase C (PKC) is involved in the inhibitory action of the cytokines. Within 1 h after the onset of hypoxia, Epo mRNA levels were markedly increased in untreated HepG2 cells as quantitated by competitive reverse transcription PCR. The cytokines IL-1 beta and TNF prevented this hypoxia-induced increase in Epo mRNA levels. In phorbol-ester-treated cells first inhibitory effects on Epo mRNA levels were observed only after 3 h. Western blot analyses revealed the presence of four isoenzymes of PKC in HepG2 cells. None of these isoenzymes was translocated in response to TNF or IL-1 beta, suggesting that the cytokines do not activate PKC in HepG2 cells. In contrast, phorbol esters translocated and, upon prolonged exposure, down-regulated PKC isoenzymes alpha and epsilon. Activation of protein kinase A by dibutyryl-cAMP partially antagonized the cytokine-dependent inhibition of Epo production but did not influence the inhibitory effect of phorbol esters. Endogenous cAMP levels in HepG2 cells were unchanged by cytokine treatment. Obviously, at least two signaling pathways exist that can confer inhibition of Epo production in HepG2 cells. One of these may be mediated by down-regulation of the PKC alpha or epsilon isoenzyme. The other pathway, however, which is triggered by IL-1 beta and TNF, is independent of PKC.
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PMID:Distinct signaling pathways mediate phorbol-ester-induced and cytokine-induced inhibition of erythropoietin gene expression. 752 38

Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.
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PMID:Hepatitis B virus immunopathogenesis. 761 25

The effect of human recombinant tumor necrosis factor alpha (h rec TNF-alpha) on the growth of Morris hepatoma 5123 implanted in the skeletal muscles of the thigh of Buffalo rats was investigated. The cytokine was repeatedly given in an intratumor administration (i.t.) in dose of 1.5 x 10(4) U once a day in regimens of four or eight days. Comparative groups consisted of animals which were given saline i.t. Control groups included healthy rats subjected to local cytokine effect. The experiments revealed an inhibitory effects of the preparation on the growth of tumors. Biometric parameters of the tumors induced indicated that the inhibition of Morris hepatoma was most effective after the eighth dose of h rec TNF-alpha. The administration of fourfold dose resulted in an initial loss of body mass increase. However, when injected eight times, the factor produced a relative tolerance reflected in minor reduction of actual body mass. The estimation of survival time in rats injected i.t. with h rec TNF-alpha, compared to those given saline, revealed statistically significant differences at the eighth repeated dose.
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PMID:Evaluation of biometric parameters of Morris hepatoma after application of human recombinant tumor necrosis factor. 761 82

An eukaryotic expression vector containing tumor necrosis factor alpha (TNF alpha) gene (psVK3-tnf) was transduced into hepatocellular carcinoma (HCC) cell line, SMMC7721, by calcium phosphate coprecipation method. The TNF-gene-transduced SMMC7721 cell began to secrete TNF after 24h (50 0/ml), reached peak level at 48-72h (90U/ml), and declined after 96h (40U/ml). Three weeks after the pSVK3-tnf DNA entrapped with calcium phosphate was introduced directly into subcutaneous nodules of human HCC in nude mice (treated mice), the growth of HCC was significantly delayed as compared to the pSVK3 group (control mice) (2.5 +/- 1.6 cm vs. 3.2 +/- 1.8 cm, n = 6, P < 0.05). There was a transient increase in TNF alpha level in peripheral blood in the treated but not in the control mice. The survival time of the treated mice was markedly prolonged as compared to the control (44.0 +/- 3.3d vs. 28.2 +/- 2.0d, n = 6, P < 0.01). The above results suggest that TNF alpha gene transfer might be a hopeful therapy for HCC.
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PMID:[Preliminary studies on the effects of tumor necrosis factor gene transfer on the growth of human hepatocellular carcinoma cells in nude mice]. 765 17

Tumor necrosis factor alpha (TNF alpha) was measured with an enzyme-linked immunosorbent assay. TNF alpha levels in peripheral blood of patients with twenty-one cases of chronic persistent hepatitis (7.3 +/- 9.5 micrograms/L), fourty-two cases of chronic active hepatitis (15.4 +/- 31.1 micrograms/L), one hundred and six cases of liver cirrhosis (11.1 +/- 17.7 micrograms/L) and one hundred and ten cases of parimary hepatocellular carcinoma (10.9 +/- 13.3 micrograms/L) was significantly increased when compared with normal controls (4.3 +/- 2.9 micrograms/L) (P < 0.01). There was significant correlation between tumor necrosis factor alpha levels and ALT elevation and also between TNF alpha levels and bilirubin contents more than 100 mumol/L in chronic hepatitis patients. Tumor necrosis factor alpha levels was also significantly in HBV concomitant with HCV and/or HDV infection than in HBV infection alone. There was no correlation in tumor necrosis factor alpha levels and AFP concentrations. These findings show that tumor necrosis factor participates in the activity process of liver disease.
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PMID:[Tumor necrosis factor alpha levels in patients with chronic liver diseases and its relationship to pathogenesis]. 771 14

The effect of the human recombinant tumor necrosis factor alpha (h rec TNF-alpha) on the transplantable Morris hepatoma 5123 was studied in Buffalo rats. The cytokine was repeatedly administered intratumorly (i.t.) in a dose of 1.5 x 10(4) U once a day in a cycle of four and eight days. The control groups consisted of animals given saline i.t. The experiments revealed an inhibitory effect of the h rec TNF-alpha upon the growth of neoplastic tumors. The biometric parameters of the tumors indicated that the inhibition of the Morris hepatoma was most effective after eight repeated doses of TNF. After injections of TNF-alpha, the tumors presented extensive hemorrhagic necrosis, the regressive alterations being found mainly in the central and intermediate tumor zones. In the early phase of the tumor growth, neoplastic tissue necrosis prevailed, as well as hemorrhages within the necrotic masses, necrosis of the blood vessel walls and thrombi in their lumina. In the later period, numerous fibres of the fibrous tissue, richly vascularized, occurred in the peripheral and intermediate zones. Clusters of eosinophilic granulocytes and macrophages with apoptotic bodies in the cytoplasm were seen on the border of the necrotic foci.
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PMID:Inhibitory effect of the human recombinant tumor necrosis factor on the growth of the Morris hepatoma in rats. 771 25

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

An important objective for patients with unresectable hepatocellular carcinoma (HCC) is the development of effective chemotherapy. We administered a combination of biological response modifiers and anticancer agents to 24 patients with unresectable HCC. Each case had an implanted infuser port which was connected to a catheter placed in the hepatic artery for the intraarterial (i.a.) administration of chemotherapy. The following agents were administered to each patient: recombinant interleukin-2 (800,000 JRU/day infused i.a. continuously for 6 days/week); OK-432 (5 KE injected i.a. twice in 4 weeks and i.m. three times per week); Adriamycin (10 mg injected i.a. twice in 4 weeks); cyclophosphamide (300 mg injected i.a. twice in 4 weeks), and famotidine (40 mg/day administered orally). Objective response was assessed according to tumor size measured by computed tomography and angiography before and after treatment. We observed a complete response (CR) in 4, partial response (PR) in 3, minor response (MR) in 7, no change (NC) in 7, and progressive disease (PD) in 3. The response rate (CR+PR+MR) was 58.3%. The overall 2-year survival rate was 52%. The 2-year survival rate of the responders (CR+PR+MR) was 80%, while that of the non-responders (NC+PD) was 0%. There was a significant difference between the responders and non-responders in respect to survival rate (P < 0.05). The percentages of CD25+ cells, CD56+ cells, and Leu7-CD16+ cells and NK activity in the peripheral blood showed a significant increase following the regimen. Serum levels of tumor necrosis factor alpha TNF alpha rose after the initiation of OK-432. TNF alpha levels were higher in the responders than in the non-responders. Adverse effects included high fever (all patients) and severe transient hypotension (15 patients) that was controlled by conservative therapy. Combined immunochemotherapy administered intraarterially may be a new strategy for treating unresectable HCC.
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PMID:Intraarterial combined immunochemotherapy for unresectable hepatocellular carcinoma: preliminary results. 812 88

Hepatocytes respond to inflammatory stimuli by changing the synthesis and N-glycosylation of acute phase plasma proteins (APP). So far, interleukin (IL) 6, transforming growth factor beta (TGF beta), tumor necrosis factor alpha (TNF) and IL-1 have been found to control N-glycosylation patterns of APP. Cytokines either increased (type I) or decreased (type II) the ratio of bi-relative to more branched N-glycans on APP. In this study, we describe the effect of leukemia inhibitory factor (LIF), interferon gamma (INF gamma) and dexamethasone (dex) on production of alpha 1-protease inhibitor (PI) and alpha 1-antichymotrypsin (ACT) and on glycosylation of PI in the human hepatoma cell line HepG2. Cytokines and dex were used separately and in various combinations including also IL-6 and TGF beta. Production of the antiproteases was quantitated by immunoelectrophoresis of the proteins accumulated in the culture medium. Glycosylation pattern of PI was assessed by crossed immunoaffinity electrophoresis (CIAE) with Concanavalin A (Con A) as a ligand. The production of ACT and PI was increased by LIF, decreased by INF gamma and unaffected by dex. LIF and INF gamma each like IL-6, decreased PI-Con A reactivity while dex like TGF beta enhanced PI-Con A reactivity. Combination of dex with LIF yielded additive effects while combination of dex with either INF gamma, L-6 or TGF beta acted synergistically on PI-Con A reactivity. Combinations of multiple cytokines and dex produced additive, inhibitory or synergistic effects. The type of glycosylation profile of PI secreted by HepG2 cells depended on the composition and amounts of interacting cytokines and dex.
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PMID:Leukemia inhibitory factor, interferon gamma and dexamethasone regulate N-glycosylation of alpha 1-protease inhibitor in human hepatoma cells. 839 65

Inflammation is accompanied by an increase in the plasma levels of a number of proteins collectively known as acute-phase reactants (APRs). Serum amyloid P component (SAP) is a major mouse APR: hepatic SAP mRNA and plasma SAP protein concentrations increase by up to 20-fold in mice undergoing an inflammatory response. In-vitro studies, using primary hepatocyte cultures, have previously shown that SAP mRNA and protein levels increase in response to stimulation with a variety of cytokines such as monocyte-conditioned medium (MCM), interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta). In this report, we have examined a mouse hepatoma cell line in which SAP gene regulation closely resembles that of primary hepatocytes. Accumulation of SAP mRNA in the +/+ Li mouse hepatoma cell line after stimulation with MCM, IL-1, IL-6 and the combination of IL-1 and IL-6 was demonstrated. This increase in the cellular content of SAP mRNA did not require new protein synthesis and was at least partially due to an increase in the transcription rate of the SAP gene.
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PMID:Regulation of mouse serum amyloid P gene expression by cytokines in vitro. 845 73


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