Ribavirin inhibits protein synthesis and cell proliferation induced by mitogenic factors in primary human and rat hepatocytes

Ilyin, Gennady; Langouët, Sophie; Rissel, Mary; Delcros, Jean‐Guy; Guillouzo, André; Guguen‐Guillouzo, Christiane

doi:10.1002/hep.510270630

Cited by 24 publications

(12 citation statements)

References 33 publications

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“…In accordance to our previous observations (29,37), adult rat hepatocytes stimulated with EGF 4 h after seeding and throughout culture, started to incorporate [ 3 H]thymidine between 42 and 54 h, reaching a maximum around 72 h (data not shown). In unstimulated cultures, incorporation of the tracer was very low.…”

Section: Amounts Of the Cdk Inhibitors Decrease During Development Ofsupporting

confidence: 92%

Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth

Ilyin

Glaise

Gilot

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Unlike a large number of cell types that undergo terminal differentiation associated with permanent withdrawal from the cell cycle, mature quiescent hepatocytes retain high proliferative potential. We report here a specific behavior of members of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors during development of the rat liver and proliferation of normal hepatocytes. Expression of p21, p27, and p57 transcripts and proteins was downregulated during the differentiation process to low or undetectable levels in adult liver. In contrast to p27, p21 protein increased in a mitogen-dependent manner in isolated hepatocytes and its expression pattern correlated with that of cyclin D1. In proliferating hepatocytes, p21 was predominantly associated with cyclin D1, these proteins were colocalized in the nucleus and p21-associated retinoblastoma protein (pRb) kinase activity increased in parallel with that of cyclin D1. Overexpression of p21 in mitogen-stimulated hepatocytes reduced DNA synthesis. In contrast, inhibition of p21 expression by antisense or small interfering RNAs oligonucleotides accelerated S phase entry. Finally, expression of p21 and cyclin D1, but not p27 proteins was regulated by MAPK kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase-ferric-reducing ability power/mammalian target of rapamycin signal transduction pathways. In conclusion, these results demonstrate a specific and differential regulation of p21 and p27 during hepatocyte differentiation and proliferation that may contribute to the control of quiescent differentiated hepatic cell proliferating activity.

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Section: Amounts Of the Cdk Inhibitors Decrease During Development Ofsupporting

confidence: 92%

Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth

Ilyin

Glaise

Gilot

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Ribavirin might affect signal transduction pathways by exerting nonspecific effects on cell proliferation and protein synthesis. However, the minimal ribavirin dose needed to significantly affect cell proliferation and protein synthesis was 500 M after 24 h and 60 M after 72 h in primary human hepatocytes (14).…”

Section: Discussionmentioning

confidence: 95%

Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

Schlosser¹,

Schüler²,

Berg³

et al. 2003

Antimicrob Agents Chemother

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The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation ocurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds.

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“…In fact it has been demonstrated that ribavirin also inhibits protein synthesis in cultured hepatocytes [Ilyin et al, 1998]. …”

Section: Discussionmentioning

confidence: 99%

Ribavirin inhibits DNA, RNA, and protein synthesis in PHA‐stimulated human peripheral blood mononuclear cells: Possible explanation for therapeutic efficacy in patients with chronic HCV infection

Meier

Bürger

Mihm

et al. 2002

Journal of Medical Virology

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The treatment of choice for patients infected chronically with HCV is the combination of IFN-alpha and ribavirin. Monotherapy with ribavirin leads to a clinical and histological improvement, but its exact mechanism of action is unknown. Therefore, the effect of ribavirin on synthesis of inflammatory cytokines and on apoptosis in stimulated peripheral blood mononuclear cells (PBMCs) was investigated. PBMCs were isolated from the blood of HCV infected patients and from healthy volunteers. The effect of ribavirin on IFN-gamma and IL-1beta release in the supernatant of unstimulated and phytohemagglutinin (PHA) stimulated PBMCs was investigated by enzyme linked immunosorbent assay (ELISA). The effect on total DNA, RNA, and protein synthesis was analyzed by measurement of 3H-thymidine, 3H-uridine and 3H-leucine incorporation into cellular macromolecules. Ribavirin led to a dose-dependent decrease of the IFN-gamma but an increase of IL-1beta release into the supernatant of PHA-stimulated PBMCs. At the same time, a dose-dependent decrease of total DNA, RNA, and protein synthesis in cultures of PHA-stimulated PBMCs was demonstrated. These effects could be compensated by the addition of equimolar amounts of guanosine. The rate of apoptotic CD45+ and CD14+ cells in PBMCs cultures increased in a dose-dependent manner. Our data suggest that ribavirin administration to chronically HCV-infected patients could lead to a decrease of the synthesis of proinflammatory cytokines (e.g., IFN-gamma) by an inhibition of total DNA-, RNA-, and protein-synthesis and by induction of apoptosis in the cells of the inflammatory infiltrate. Furthermore, ribavirin could influence the synthesis of viral particles in the hepatocytes.

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Ribavirin inhibits protein synthesis and cell proliferation induced by mitogenic factors in primary human and rat hepatocytes

Cited by 24 publications

References 33 publications

Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth

Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth

Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

Ribavirin inhibits DNA, RNA, and protein synthesis in PHA‐stimulated human peripheral blood mononuclear cells: Possible explanation for therapeutic efficacy in patients with chronic HCV infection

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