Inhibition of interferon-α-induced signaling by hyperosmolarity and hydrophobic bile acids

2010 ◽  
Vol 391 (10) ◽  
Author(s):  
Dirk Graf ◽  
Katrin Haselow ◽  
Ivo Münks ◽  
Johannes G. Bode ◽  
Dieter Häussinger
Keyword(s):  
Protein Expression ◽  
Bile Acids ◽  
Hepatoma Cell ◽  
Protein A ◽  
Sodium Taurocholate ◽  
Inhibitory Effect ◽  
Interferon Α ◽  
Hepatoma Cell Line ◽  
Human Hepatoma Cell ◽  
Mrna And Protein Expression

Abstract Apart from viral conditions, host factors such as elevated bile acid concentrations are determinants of successful interferon-α (IFN-α) treatment in patients with chronic hepatitis C or B. The present study demonstrates that hydrophobic bile acids inhibit Jak1- and Tyk2-phosphorylation, which lead to blockade of STAT1-mediated IFN-α-signaling in the sodium-taurocholate cotransporting peptide (NTCP)-transfected human hepatoma cell line HepG2, resulting in a decreased mRNA and protein expression of IFN-stimulated genes such as myxovirus resistance protein A (MxA) or dsRNA-activated protein kinase (PKR). In addition, hyperosmotic stress leads to an inhibition of IFN-α-induced Jak1- and Tyk2-phosphorylation, and STAT1/STAT2-phosphorylation and gene expression. This inhibitory effect of hydrophobic bile acids or hyperosmolarity is not due to caspase-mediated cleavage or lysosomal degradation of the cognate receptors or to the generation of oxidative stress, activation of p38- or Erk-mediated MAPK pathways or phosphatase activity. Preincubation with the organic osmolyte betaine blocked the inhibitory effect of bile acids or hyperosmolarity on MxA protein expression, but had no effect on transcript levels or activation of STAT1, suggesting that betaine mediates its effects on MxA expression at a translational or post-translational level. Our findings could provide a rationale for betaine use in cholestatic HBV/HCV patients undergoing interferon therapy.

scholarly journals HBV Upregulates CtBP2 Expression via the X Gene

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Xinghui Liu ◽  
Chengliang Zhu ◽  
Jie Li ◽  
Fengxia Xu ◽  
Gang Huang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Hepatoma Cell ◽  
Infectious Clone ◽  
Single Gene ◽  
Gene Promoter ◽  
Hepatoma Cell Line ◽  
Human Hepatoma Cell ◽  
Activation Effect ◽  
Mrna And Protein Expression ◽  
X Gene

Background. Hepatitis B virus (HBV) infection causes acute and chronic liver diseases that can eventually develop into cirrhosis and hepatocellular carcinoma (HCC), but the carcinogenesis of HBV is not fully understood. Carboxyl-terminal-binding protein 2 (CtBP2) plays an important role in tumorigenesis and progression. The aim of this study was to investigate the effect of HBV on CtBP2 expression and to explore its mechanism.Methods. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting were used to evaluate the CtBP2 mRNA and protein expression levels in tissues and cells. The HBV infectious clone pHBV1.3 and plasmids expressing a single gene of the HBV genome were cotransfected with the CtBP2 gene promoter pGL3-CtBP2 into the human hepatoma cell line HepG2, and luciferase activity was determined using a luminometer.Results. CtBP2 expression was higher in HBV-related HCC tissues than in paracancerous tissues. CtBP2 expression was higher in HepG2.2.15 cells integrated with the HBV genome than in HepG2 cells. pHBV1.3 upregulated CtBP2 mRNA and protein expression. The HBV X gene significantly activated CtBP2 gene promoter activity, and CtBP2 mRNA and protein expression were upregulated by the HBV X gene. This activation effect was enhanced by the increase in the dose of the X gene, showing metrological dependence.Conclusion. HBV may be involved in the occurrence and development of HCC by upregulating CtBP2 expression.

Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3743-3747 ◽  
Author(s):  
Hyogo Horiguchi ◽  
Fujio Kayama ◽  
Etsuko Oguma ◽  
William G. Willmore ◽  
Pavel Hradecky ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Damage ◽  
Hepatoma Cell ◽  
Inhibitory Effect ◽  
Binding Activity ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Toxic Exposure ◽  
Human Hepatoma Cell ◽  
Simultaneous Exposure

Abstract Both toxic exposure to cadmium and cancer therapy with cisplatin (CDDP) can induce anemia in patients owing to the insufficient production of erythropoietin (EPO). Therefore, the effects of cadmium chloride (Cd) and CDDP in the Hep3B human hepatoma cell line, which up-regulates EPO expression in response to hypoxia and cobalt (Co), were investigated. The induction of binding activity of the HIF-1 transcription factor and EPO mRNA expression and protein production were suppressed by Cd and CDDP in a dose-dependent manner with no apparent cell damage. Mercuric chloride also suppressed hypoxia- and Co-induced EPO production, mRNA expression, and HIF-1 binding in a manner similar to Cd and CDDP, whereas zinc chloride suppressed Co-induced EPO production, mRNA expression, and HIF-1 binding but did not affect hypoxia induction or that observed after simultaneous exposure to hypoxia and Co. In contrast, lead and tin salts had no effect on HIF-1 activation or EPO expression. These results indicate that Cd and CDDP have a strong and specific inhibitory effect on hypoxia- and Co-induced signaling and EPO induction in hepatic cells. It is likely that these agents cause anemia by directly impacting EPO production in the kidney.

scholarly journals Role of hydrogen peroxide in hypoxia-induced erythropoietin production

1994 ◽  
Vol 303 (2) ◽  
pp. 507-510 ◽  
Author(s):  
J Fandrey ◽  
S Frede ◽  
W Jelkmann
Keyword(s):  
Hepg2 Cells ◽  
Hepatoma Cell ◽  
Inhibitory Effect ◽  
Hepatoma Cell Line ◽  
Human Hepatoma Cell ◽  
Endogenous Production ◽  
Hepatoma Cell Line Hepg2 ◽  
Haem Protein ◽  
Exogenous H2o2

The addition of exogenous H2O2 inhibited hypoxia-induced erythropoietin (Epo) production in the human hepatoma cell line HepG2. Likewise, elevation of endogenous H2O2 levels by the addition of menadione or the catalase inhibitor, aminotriazole, dose-dependently lowered Epo production. The inhibitory effect of exogenous H2O2 on Epo formation could be completely overcome by co-incubation with catalase. When GSH levels in HepG2 cells were lowered, Epo production was more susceptible to H2O2-induced inhibition, indicating that H2O2 might affect thiol groups in regulatory proteins. Endogenous production of H2O2 in HepG2 cells was dependent on the pericellular O2 tension, being lowest under conditions of hypoxia. Our results support the hypothesis that an H2O2-generating haem protein might be part of the O2 sensor that controls Epo production. High H2O2 levels under conditions of normoxia suppress, whereas lower levels in hypoxic cells allow epo gene expression.

scholarly journals Effects of Fresh Royal Jelly on the Proliferation of Human Hepatoma Cell Line SMMC-7721

1970 ◽  
Vol 1 (2) ◽  
Author(s):  
Mingmin Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Line ◽  
Royal Jelly ◽  
Hepatoma Cell ◽  
Inhibitory Effect ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cell ◽  
Human Hepatoma Cell Line

Objective: To investigate the effect of fresh royal jelly on the proliferation of human hepatoma cell line SMMC-7721. Methods: We found that the administration of fresh royal jelly could alleviate the condition of hepatocellular carcinoma patients in a certain extent. The human hepatocellular carcinoma cell line SMMC-7721 was cultured in vitro. MTT colorimetric method was used to treat fresh cells and serum containing human serum. The effect of SMMC-7721 proliferation was observed. Results: The aqueous solution of fresh royal jelly had a certain effect on the proliferation of hepatoma cell line SMMC-7721 in a dose-dependent manner. The serum containing fresh royal jelly could inhibit the proliferation of human hepatoma cell line SMMC-7721, and its inhibitory effect showed dose-dependent. Conclusion: The serum containing fresh royal jelly has a significant inhibitory effect on the proliferation of human hepatoma cell line SMMC-7721 and its anti-cancer effect may be derived from its metabolites or stimulating the formation of immune-reactive substances in the body, in which in the clinical treatment of liver cancer and research have a certain value.

Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3743-3747 ◽  
Author(s):  
Hyogo Horiguchi ◽  
Fujio Kayama ◽  
Etsuko Oguma ◽  
William G. Willmore ◽  
Pavel Hradecky ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Damage ◽  
Hepatoma Cell ◽  
Inhibitory Effect ◽  
Binding Activity ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Toxic Exposure ◽  
Human Hepatoma Cell ◽  
Simultaneous Exposure

Both toxic exposure to cadmium and cancer therapy with cisplatin (CDDP) can induce anemia in patients owing to the insufficient production of erythropoietin (EPO). Therefore, the effects of cadmium chloride (Cd) and CDDP in the Hep3B human hepatoma cell line, which up-regulates EPO expression in response to hypoxia and cobalt (Co), were investigated. The induction of binding activity of the HIF-1 transcription factor and EPO mRNA expression and protein production were suppressed by Cd and CDDP in a dose-dependent manner with no apparent cell damage. Mercuric chloride also suppressed hypoxia- and Co-induced EPO production, mRNA expression, and HIF-1 binding in a manner similar to Cd and CDDP, whereas zinc chloride suppressed Co-induced EPO production, mRNA expression, and HIF-1 binding but did not affect hypoxia induction or that observed after simultaneous exposure to hypoxia and Co. In contrast, lead and tin salts had no effect on HIF-1 activation or EPO expression. These results indicate that Cd and CDDP have a strong and specific inhibitory effect on hypoxia- and Co-induced signaling and EPO induction in hepatic cells. It is likely that these agents cause anemia by directly impacting EPO production in the kidney.

scholarly journals Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis in the Human Hepatoma Cell Line HepaRG

Foods ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Julia Waizenegger ◽  
Josephin Glück ◽  
Marcus Henricsson ◽  
Claudia Luckert ◽  
Albert Braeuning ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cell Line ◽  
Pyrrolizidine Alkaloids ◽  
Hepatoma Cell ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Hepatoma Cell Line ◽  
Human Hepatoma ◽  
Human Hepatoma Cell

1,2-unsaturated pyrrolizidine alkaloids (PAs) belong to a group of secondary plant metabolites. Exposure to PA-contaminated feed and food may cause severe hepatotoxicity. A pathway possibly involved in PA toxicity is the disturbance of bile acid homeostasis. Therefore, in this study, the influence of four structurally different PAs on bile acid homeostasis was investigated after single (24 h) and repeated (14 days) exposure using the human hepatoma cell line HepaRG. PAs induce a downregulation of gene expression of various hepatobiliary transporters, enzymes involved in bile acid synthesis, and conjugation, as well as several transcription regulators in HepaRG cells. This repression may lead to a progressive impairment of bile acid homeostasis, having the potential to accumulate toxic bile acids. However, a significant intracellular and extracellular decrease in bile acids was determined, pointing to an overall inhibition of bile acid synthesis and transport. In summary, our data clearly show that PAs structure-dependently impair bile acid homeostasis and secretion by inhibiting the expression of relevant genes involved in bile acid homeostasis. Furthermore, important biliary efflux mechanisms seem to be disturbed due to PA exposure. These mole-cular mechanisms may play an important role in the development of severe liver damage in PA-intoxicated humans.

scholarly journals Nitric oxide-mediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP

2011 ◽  
Vol 300 (2) ◽  
pp. G364-G370 ◽  
Author(s):  
Christopher M. Schonhoff ◽  
Umadevi Ramasamy ◽  
M. Sawkat Anwer
Keyword(s):  
Nitric Oxide ◽  
Protein Function ◽  
Hepatoma Cell ◽  
Sodium Taurocholate ◽  
Rat Hepatocytes ◽  
Hepatoma Cell Line ◽  
Human Hepatoma Cell ◽  
Bile Formation ◽  
Noncompetitive Inhibition ◽  
Cysteine Thiols

The sodium-taurocholate (TC) cotransporting polypeptide (NTCP) facilitates bile formation by mediating sinusoidal Na+-TC cotransport. During sepsis-induced cholestasis, there is a decrease in NTCP-dependent uptake of bile acids and an increase in nitric oxide (NO) levels in hepatocytes. In rat hepatocytes NO inhibits Na+-dependent uptake of taurocholate. The aim of this study was to extend these findings to human NTCP and to further investigate the mechanism by which NO inhibits TC uptake. Using a human hepatoma cell line stably expressing NTCP (HuH-NTCP), we performed experiments with the NO donors sodium nitroprusside and S-nitrosocysteine and demonstrated that NO inhibits TC uptake in these cells. Kinetic analyses revealed that NO significantly decreased the Vmax but not the Km of TC uptake by NTCP, indicating noncompetitive inhibition. NO decreased the amount of NTCP in the plasma membrane, providing a molecular mechanism for the noncompetitive inhibition of TC uptake. One way that NO can modify protein function is through a posttranslational modification known as S-nitrosylation: the binding of NO to cysteine thiols. Using a biotin switch technique we observed that NTCP is S-nitrosylated under conditions in which NO inhibits TC uptake. Moreover, dithiothreitol reversed NO-mediated inhibition of TC uptake and S-nitrosylation of NTCP, indicating that NO inhibits TC uptake via modification of cysteine thiols. In addition, NO treatment led to a decrease in Ntcp phosphorylation. Taken together these results indicate that the inhibition of TC uptake by NO involves S-nitrosylation of NTCP.

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