Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2

Lesnikov, Vladimir; Gorden, Nicholas T.; Fausto, Nelson; Spaulding, Emily; Campbell, Jean S.; Shulman, Howard M.; Fleming, Robert E.; Deeg, H. Joachim

doi:10.1007/s10495-008-0233-6

Cited by 8 publications

(8 citation statements)

References 30 publications

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“…We had shown previously that hepatic responses similar to those observed with allogeneic cells were also observed with the use of agonistic anti-Fas antibody [17]. Specifically, we had shown that aFas (JO2, at 250–1000 ng/mL for murine cells; CH11, at 250–500 ng /mL for human cells) effectively induced apoptosis in murine (NMH) and human (HH4) hepatocyte lines, respectively [14].…”

Section: Resultsmentioning

confidence: 71%

Allogeneic Transplantation, Fas Signaling, and Dysregulation of Hepcidin

Karoopongse

et al. 2013

Biology of Blood and Marrow Transplantation

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Hepatic iron overload is common in patients undergoing hematopoietic cell transplantation. We showed previously in a murine model that transplantation of allogeneic T cells induced iron deposition and down-regulation of hepcidin (Hamp) in hepatocytes. We hypothesized that hepatic injury was related to disrupted iron homeostasis triggered by the interaction of Fas-ligand, expressed on activated T cells, with Fas on hepatocytes. In the current study, we determined the effects of modified expression of the Flice inhibitory protein (FLIP long [FLIPL]), which interferes with Fas signaling, on the impact of Fas-initiated signals on the expression of IL-6 and Stat3 and their down-stream target, Hamp. To exclude a possible contribution by other pathways, we used agonistic anti-Fas antibodies (rather than allogeneic T cells) to trigger Fas signaling. Inhibition of FLIPL by RNA interference resulted, as expected, in enhanced hepatocyte apoptosis in response to Fas signals, but also in decreased levels of IL-6, Stat3 and Hamp. In contrast, over-expression of FLIPL protected hepatocytes against agonistic anti-Fas antibody-mediated apoptosis, and increased the levels of IL-6 and Stat3, thereby maintaining the expression of Hamp in an NF-κB-dependent fashion. In vivo over-expression of FLIPL in the liver via hydrodynamic transfection, similarly, interfered with Fas-initiated apoptosis and prevented down-regulation of IL-6, Stat3 and Hamp. These data indicate that Fas-dependent signals alter the regulation of iron homeostasis and suggest that signals initiated by Fas may contribute to peri-transplant iron accumulation.

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Section: Resultsmentioning

confidence: 71%

Allogeneic Transplantation, Fas Signaling, and Dysregulation of Hepcidin

Karoopongse

et al. 2013

Biology of Blood and Marrow Transplantation

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“…We had shown previously that Fas-initiated hepatocyte injury was attenuated or prevented by apotransferrin. 13,16 Since alloactivated T lymphocytes express Fas ligand, and Fas signaling is involved in GVHD, 17,18 we postulated that pretreatment of NOD/SCID mice with apotransferrin before histoincompatible T-cell infusion would interfere with hepatic injury and liver iron deposition. Results illustrated in Figure 1C through F support this hypothesis by showing substantial reduction in hepatocyte apoptosis and serum transaminase elevations.…”

Section: Resultsmentioning

confidence: 99%

“…Results illustrated in Figure 1C through F support this hypothesis by showing substantial reduction in hepatocyte apoptosis and serum transaminase elevations. Thus, chelation of iron by apotransferrin, 19 or possibly transferrin-mediated antiapoptotic signals, 16 counteracted iron overload and protected tissues against allogeneic histoincompatible T cell-dependent injury. These data support earlier reports of a GVHD prophylactic effect of apoTf.…”

Section: Resultsmentioning

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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“…TfR2 is a close homologue of TfR1 showing 45% identity in the extracellular domain [3]. TfR2 is predominantly found in tissues responsible for regulating iron metabolism such as the liver and small intestine whereas TfR1 distribution is less restricted [4–5]. TfR2 has an approximately 25-fold reduced holo-Tf affinity compared to TfR1 and is believed to function in overall iron metabolism in addition to cellular iron uptake [6].…”

Section: Introductionmentioning

confidence: 99%

The intracellular trafficking pathway of transferrin

Mayle

Kamei

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

360

326

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Background Transferrin (Tf) is an iron-binding protein that facilitates iron-uptake in cells. Iron-loaded Tf first binds to the Tf receptor (TfR) and enters the cell through clathrin-mediated endocytosis. Inside the cell, Tf is trafficked to early endosomes, delivers iron, and then is subsequently directed to recycling endosomes to be taken back to the cell surface. Scope of Review We aim to review the various methods and techniques that researchers have employed for elucidating the Tf trafficking pathway and the cell-machinery components involved. These experimental methods can be categorized as microscopy, radioactivity, and surface plasmon resonance (SPR). Major Conclusions Qualitative experiments, such as total internal reflectance fluorescence (TIRF), electron, laser-scanning confocal, and spinning-disk confocal microscopy, have been utilized to determine the roles of key components in the Tf trafficking pathway. These techniques allow temporal resolution and are useful for imaging Tf endocytosis and recycling, which occur on the order of seconds to minutes. Additionally, radiolabeling and SPR methods, when combined with mathematical modeling, have enabled researchers to estimate quantitative kinetic parameters and equilibrium constants associated with Tf binding and trafficking. General Significance Both qualitative and quantitative data can be used to analyze the Tf trafficking pathway. The valuable information that is obtained about the Tf trafficking pathway can then be combined with mathematical models to identify design criteria to improve the ability of Tf to deliver anticancer drugs.

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Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2

Cited by 8 publications

References 30 publications

Allogeneic Transplantation, Fas Signaling, and Dysregulation of Hepcidin

Allogeneic Transplantation, Fas Signaling, and Dysregulation of Hepcidin

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

The intracellular trafficking pathway of transferrin

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