Protection of human and murine hepatocytes against Fas-induced death by transferrin and iron

Lesnikov, Vladimir; Abbasi, Nissa; Lesnikova, Marina; Lázaro, Catherine A.; Campbell, Jean S.; Fausto, Nelson; Deeg, H. Joachim

doi:10.1007/s10495-005-3086-2

Cited by 11 publications

(24 citation statements)

References 27 publications

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“…Total RNA was isolated and cDNA synthesized using the MACS One-Step cDNA Synthesis kit (Miltenyi Biotec, Auburn, CA) as instructed and as previously described. 11 Quantitative polymerase chain reaction (PCR) was carried out using the comparative C t method as described by Livak and Schmittgen 12 and as used previously. 13 Gene expression assays (Applied Biosystems, Foster City, CA) were used to analyze expression of the murine hepcidin gene hamp1 (Mm00519025_m1) and FPN1 (fpn1; Mm00489837_m1).…”

Section: Methodsmentioning

confidence: 99%

Transplantation of allogeneic T cells alters iron homeostasis in NOD/SCID mice

Bair

Spaulding

Parkkinen

et al. 2009

Blood

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Iron overload is common in patients undergoing allogeneic hematopoietic cell transplantation (HCT), but the mechanisms leading to overload are unknown. Here, we determined iron levels and the expression of iron regulatory proteins in the liver and gut of nonobese diabeticsevere combined immunodeficient (NOD/ SCID) mice that underwent transplantation with syngeneic (histocompatible) or allogeneic (histoincompatible) T lymphocytes. Infusion of histoincompatible T cells resulted in a significant rise in serum iron levels and liver iron content. IntroductionIron overload is common in patients undergoing hematopoietic cell transplantation (HCT). 1-3 Many of these patients develop iron overload even without heavy red cell transfusion support; the mechanisms are largely unknown. High-dose conditioning preceding HCT may result in hyperferremia and increased non-transferrinbound iron, in association with the cessation of erythropoietic activity. 4,5 In many patients hyperferremia persists after HCT, 1,2 suggesting aberrant iron release into the circulation.The major regulator of iron release into the circulation is hepcidin (Hamp), secreted mainly by the liver. 6 Hepcidin binds to the iron transporter ferroportin 1 (Fpn), expressed on enterocytes and macrophages, which delivers iron from inside the cell to the circulation. 7 Hepcidin binding results in internalization and cytoplasmic degradation of ferroportin. As both the intestinal tract and liver are targets of graft-versus-host disease (GVHD), 2,8,9 we hypothesized that one effect of allogeneic transplantation may be direct or indirect interference by T lymphocytes with the expression or function of iron regulatory proteins in liver and gut, thereby contributing to iron overload. Here we characterized Hamp and Fpn expression and dietary iron uptake in a murine model of histoincompatible allogeneic T-lymphocyte transplantation. MethodsFemale NOD/LtSz-scid/scid (NOD/SCID [H-2d]), C57BL/6J (H-2b), and BALB/cJ mice (H-2d) were purchased from The Jackson Laboratory (Bar Harbor, ME). NOD/SCID mice were maintained in a pathogen-free environment and kept on normal chow (iron content ϳ35 ppm) or chow with low (Յ 1 ppm) or high (30 000 ppm) iron content (Test Diets, Richmond, IN), for 14 to 28 days before transplantation. Histocompatible Mice were euthanized at 7 or 14 days after transplantation (3-6 weeks after initiating a particular diet) by CO 2 inhalation. Blood was collected via cardiac puncture and total serum iron was measured. Hepatic iron content was determined using a colorimetric assay as described. 10 Tissue for histology was fixed in 10% formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin and with Perl Prussian blue to detect iron deposition.Hepatocyte suspensions were generated by mincing and straining liver tissue through a 75-m mesh. Enterocytes were obtained by scraping the mucosa off the inverted duodenum and mincing and straining through a 75-m mesh. Total RNA was isolated and cDNA synthesized using the MACS One-Step cDNA Sy...

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Section: Methodsmentioning

confidence: 99%

Transplantation of allogeneic T cells alters iron homeostasis in NOD/SCID mice

Bair

Spaulding

Parkkinen

et al. 2009

Blood

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“…Recently, the plasma protein transferrin was found to interfere with Fas-mediated hepatocyte death and liver failure in vivo, by decreasing pro-apoptotic and increasing antiapoptotic signals. Survival of hepatocytes stressed by Fas signals can be monitored by transferrin and iron, leading to postulate that this protein might be a target for new therapeutic applications (69).…”

Section: Expression and Regulation Of Liver Functionsmentioning

confidence: 99%

General Review on In Vitro Hepatocyte Models and Their Applications

Guguen‐Guillouzo

Guillouzo

2010

Methods in Molecular Biology

204

137

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In vitro hepatocyte models represent very useful systems in both fundamental research and various application areas. Primary hepatocytes appear as the closest model for the liver in vivo. However, they are phenotypically unstable, have a limited life span and in addition, exhibit large interdonor variability when of human origin. Hepatoma cell lines appear as an alternative but only the HepaRG cell line exhibits various functions, including major cytochrome P450 activities, at levels close to those found in primary hepatocytes. In vitro hepatocyte models have brought a substantial contribution to the understanding of the biochemistry, physiology, and cell biology of the normal and diseased liver and in various application domains such as xenobiotic metabolism and toxicity, virology, parasitology, and more generally cell therapies. In the future, new well-differentiated hepatocyte cell lines derived from tumors or from either embryonic or adult stem cells might be expected and although hepatocytes will continue to be used in various fields, these in vitro liver models should allow marked advances, especially in cell-based therapies and predictive and mechanistic hepatotoxicity of new drugs and other chemicals. All models will benefit from new developments in throughput screening based on cell chips coupled with high-content imaging and in toxicogenomics technologies.

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“…In addition to ferritin, transferrin has also been demonstrated to exert a cytoprotective function by interfering with Fas-mediated hepatocyte death and liver failure by decreasing pro-apoptotic and increasing anti-apoptotic signals (Lesnikov et al, 2004). Lesnikov et al (2005) showed in vitro in murine and human hepatocyte cell lines and in vivo in mice, that Fas-induced apoptosis is modulated by exogenous transferrin and iron. Therefore, it appears that both the transferrin molecule and iron affect multiple aspects of cell death, and that how iron is delivered to the cell greatly affects the final outcome of cellular Fas signaling.…”

Section: Yoshiga Et Al (1999)mentioning

confidence: 99%

“…It is anticipated that our understanding of the association between iron-binding proteins and apoptosis would strengthen with further research. In fact, it has been suggested that modulation of iron metabolism may be a potential approach for anti-inflammatory therapy (Pham et al, 2004;Lesnikov et al, 2005).…”

Section: Yoshiga Et Al (1999)mentioning

confidence: 99%