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 activation of proliferation of rat liver hepatic stellate cells (HSC) in cooperation with hepatocytes (PC) was studied using a coculture system and cell-conditioned media, respectively. The proliferation of HSC was followed by incorporation of [3H] thymidine and BrdU into DNA and by DNA content per culture. Strong stimulation of HSC proliferation was noticed under reduced fetal calf serum (FCS) conditions (0.2%) during a 48-hour coculture with PC, rat hepatoma, human hepatoma, and transforming growth factor (TGF)-alpha-transgenic mouse PC, respectively. The extent of stimulation was frequently higher than that observed by the addition of 10% FCS. Transformed HSC (myofibroblasts) could also be stimulated by cocultured PC, but the magnitude of activation was lower than that of (untransformed) HSC. Using radioreceptor assays, we could demonstrate significant concentrations of insulinlike growth factor (IGF)-1 (300 ng/10(6) cells x 48 hours) and quite lower concentrations of bFGF and TGF-alpha in the hepatocyte-conditioned media (PCcM), whereas IGF-2 was not detectable. With anti-IGF-1 neutralizing antibody, the stimulatory activity of PCcM could be reduced by approximately 50%. PCcM, which mimics the effects of cocultures and supports strongly the action of exogenous IGF-1 on HSC proliferation, leaving that of other cytokines (TGF-alpha, IL-1 alpha, bFGF, aFGF, TNF-alpha), added either separately or in various combinations, uninfluenced. The latter cytokines were without significant effects on HSC proliferation. The mitogenic activity of cytokine combinations containing IGF-1 could be enhanced severalfold by limiting amounts of PCcM. Maximum stimulation of cell proliferation of 40-fold above control cultures was reached by IGF-1 in combination with TGF-alpha and bFGF in presence of diluted PCcM, which is approximately 6-fold higher than in the absence of PCcM. [125I] IGF-1 added to PCcM was bound by more than 90% to carrier proteins. The results confirm in cocultures strong mitogenic activation of HSC by PC. It is suggested that IGF-1 and respective IGF-binding proteins are of great importance in the mitogenic signal transfer between hepatocytes and hepatic stellate cells.
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PMID:Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells. 759 Jun 70

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

The role of the inflammatory cytokines on glucocorticosteroid binding (GCSB) and glucocorticosteroid receptor (GR) level was studied. We incubated a B cell line--CESS--, a promonocytic cell line--U937--and a hepatoma cell line--HepG2--in the presence of varying concentrations of IL-1 beta, IL-6 and TNF-alpha for 24 hours. Glucocorticosteroid binding was determined by the method of "whole cell uptake," and characterized by Scatchard analysis. A considerable increase in the glucocorticosteroid binding was induced by all the three cytokines. Northern analysis of the glucocorticoid receptor expression demonstrates that the action of the cytokines is likely not pretranslational. Present data suggest that local imbalance in the ratio of these three cytokines in different pathological cases might influence the glucocorticosteroid sensitivity of the lymphocytes, monocytes and hepatocytes as target cells.
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PMID:Cytokine networks and corticosteroid receptors. 766 75

The cytokines, IL-1 beta, TNF-alpha, IL-6, IL-11, leukemia inhibitory factor, and ciliary neurotrophic factor, stimulate the expression of specific sets of acute phase plasma proteins in the rat hepatoma H-35 cell line. In this paper, the experimental drug suramin is shown to inhibit in a dose-dependent fashion the cell response to these cytokines, with the exception of TNF-alpha. The action of the IL-6-type cytokines is more sensitive to suramin inhibition that that of IL-1 beta. The effect of suramin is detectable within 30 min at the level of gene transcription and appears to be mediated by the impairment of receptor function and/or signal transduction, rather than by the inhibition of nucleic acid polymerases or DNA topoisomerase II. Similar analysis of human hepatoma HepG2 cells indicated a several-fold higher resistance to suramin and in inhibition that was less cytokine-specific than in H-35 cells. The data suggest that suramin has the potential not only to modulate the proliferation or differentiation of tumor cells as described previously, but also to affect a differentiated cell function. This broad pleiotropic action has to be taken into consideration when applying suramin as a therapeutic agent.
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PMID:Suramin inhibits the stimulation of acute phase plasma protein genes by IL-6-type cytokines in rat hepatoma cells. 768 32

In rat hepatoma H-35 cells, TNF-alpha, like IL-1 beta, stimulates the synthesis and secretion of type 1 acute phase plasma proteins, including alpha 1-acid glycoprotein (AGP), complement component 3 (C3), hemopexin, and haptoglobin. TNF and IL-1 in combination act additively to synergistically on the expression of AGP and C3 but not on hemopexin and haptoglobin. The cytokine stimulation of AGP and C3 genes is further enhanced by hepatocyte growth factor. The effect of TNF is mediated by the type I TNF receptor as judged from the TNF-like effect elicited by the agonist antibodies to type I but not type II TNF receptor. The data suggest that, although TNF and IL-1 share considerable overlap in their signal transduction mechanism, cytokine-specific signal pathways exist that affect a subset of acute phase plasma protein genes. A potential regulatory role is attributed to the transcription factors C/EBP beta and NF-kB based on studies on transiently transfected H-35 cells.
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PMID:TNF-alpha, IL-1 beta, and hepatocyte growth factor cooperate in stimulating specific acute phase plasma protein genes in rat hepatoma cells. 769 42

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

The presence of positive acute phase proteins within the circulation of rheumatoid arthritis patients suggests that elevated cytokine production associated with this chronic inflammatory disorder initiates the hepatic acute phase response. Cytokines produced at inflammatory lesions are believed to travel via the circulation to the liver where they induce acute phase protein production by hepatocytes. To test whether serum from rheumatoid arthritis patients contained sufficient levels of cytokines to promote an acute phase response in vitro, a bioassay was developed that employed the human hepatoma cell line Hep3B. These cells produced the acute phase protein serum amyloid A (SAA) in response to a combination of recombinant IL-1 beta and IL-6 or to monocyte conditioned medium. Serum (or plasma) from normal individuals or from rheumatoid arthritis patients did not induce SAA production by Hep3B cells. Moreover, these serum samples did not prevent SAA production induced by monocyte conditioned medium, indicating that they did not contain inhibitors of cytokine activity. Despite the inactivity of serum samples, synovial fluid samples obtained from rheumatoid arthritis patients were active in the hepatocyte bioassay and promoted SAA synthesis. One synovial fluid sample was analysed in detail to identify cytokines responsible for the SAA-inducing activity. Neutralizing antisera against IL-6 and IL-1 beta blocked this activity by > 90% whereas anti-IL1 alpha and anti-TNF-alpha sera were without effect. Absolute cytokine levels within the synovial fluid sample were determined by ELISA; IL-6, IL-beta and TNF-alpha, but not IL-1 alpha, were confirmed to be present. Moreover, the synovial fluid sample contained a large amount of the IL-1 receptor antagonist. These data indicate, therefore, that synovial fluid recovered from an inflamed joint contains all the necessary cytokines in balance with inhibitors to promote SAA production by Hep3B cells. The steady state levels of these factors within the plasma compartment, however, were insufficient to induce the acute phase response by cultured Hep3B cells, suggesting that this system does not mimic the relationship between the circulation and the liver that likely exists in rheumatoid arthritis patients.
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PMID:Synovial fluid from rheumatoid arthritis patients contains sufficient levels of IL-1 beta and IL-6 to promote production of serum amyloid A by Hep3B cells. 778 41

Hemopexin (Hx) is induced during the acute phase response (APR) by the cytokine interleukin (IL)-6. A type II IL-6 response element (RE) of the Hx gene has been characterized recently (J. Biol. Chem. (1994); 269, 12654-12661). To assess Hx gene regulation by other agents, various cytokines and growth factors were tested for their ability to induce Hx in rat hepatoma H-35 cells. IL-6-type cytokines, IL-1 beta and TNF-alpha, in contrast to transforming growth factor-beta (TGF-beta), hepatocyte growth factor and insulin significantly increased Hx gene expression. Chloramphenicol acetyltransferase (CAT) activity in H-35 cells transfected with constructs that contained the 5'-flanking Hx promoter region or multiple copies of the Hx IL-6-RE fused to the CAT gene was upregulated only by IL-6-type cytokines, although to varying degrees. These data indicate that signal transduction pathways mediated by IL-6-type cytokines but not those by IL-1 beta and TNF-alpha converge on the common Hx IL-6-RE.
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PMID:The type II hemopexin interleukin-6 response element predominates the transcriptional regulation of the hemopexin acute phase responsiveness. 785 66

Immunological and histological analyses were performed on 14 patients with hepatocellular carcinoma treated by transcatheter immunoembolization (TIE) and subsequently by hepatic resection. They were compared with the cases treated by transcatheter arterial embolization (TAE). Exceptionally high plasma levels of inflammatory cytokines, such as IL-6 and IL-8, were noted 3 hours after TIE insults in the majority of the cases. On the contrary, exceptionally high levels of TNF-alpha were also observed in some cases of TIE treatment. In addition, light microscopically, the lytic necrosis of the tumor and massive infiltration of mononuclear cells were the histological characteristics of this treatment. Interestingly, the population of the infiltrates has altered after TIE treatment. It thus consisted mainly of neutrophils in early phase, subsequently of the mixture of lymphocytes, eosinophils, and plasma cells, and finally of lymphocytes. These results may suggest that certain inflammatory responses caused by TIE may play important roles in this new therapeutic modality.
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PMID:[Immunological and histological analyses of transarterial immuno-embolization therapy (TIE) in operable patients with hepatocellular carcinoma]. 794 15

In patients with the anemia of chronic diseases, the plasma level of EPO is often low in relation to the blood hemoglobin concentration. Because infectious and inflammatory processes cause activation of cytokine-producing macrophages and lymphocytes, we investigated whether isolated inflammatory cytokines influence the synthesis of EPO in vitro. IL-1 and TNF-alpha were shown to inhibit EPO mRNA levels and EPO formation in the human hepatoma cell cultures HepG2 and Hep3B, and to lower EPO formation in isolated perfused rat kidneys. IFN-alpha and IFN-beta also induced some inhibition of EPO production in HepG2 cultures. IL-3, TGF-beta 2, and IFN-gamma did not inhibit. IL-6 stimulated the production of EPO in Hep3B cells but was ineffective in HepG2 cells and lowered EPO production in isolated perfused rat kidneys. IL-1, TNF-alpha, and possibly other cytokines could contribute to defective EPO production in renal and nonrenal immune responses.
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PMID:Inhibition of erythropoietin production by cytokines. Implications for the anemia involved in inflammatory states. 818 37


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