Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat

Sheikh, Nadeem; Dudás, József; Ramadori, Giuliano

doi:10.1038/labinvest.3700553

Cited by 84 publications

(95 citation statements)

References 65 publications

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“…These data confirm previous studies [35][36][37] in different rat models of liver injury, such as partial hepatectomy, CCl 4 administration, liver irradiation and turpentine oil-induced acute-phase response, that hepcidin-and Hjv-gene expression changes in the liver occur simultaneously and in an opposite direction. Specifically, when rats or mice are treated with GD intraperitoneally, hepcidin-gene expression is upregulated, whereas Hjv-and Fpn-1-gene expression are downregulated.…”

Section: Discussionsupporting

confidence: 80%

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi

Ahmad

Ramadori

et al. 2009

Laboratory Investigation

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The liver and the spleen are the organs in which cellular material and aged erythrocytes are eliminated from the blood. Within the liver, Kupffer cells (KCs) are mainly responsible for this task, as such KCs have a pivotal role in iron metabolism. The aim of this study is to investigate the changes of hepatic gene expression in two models of KC phagocytosis. Gadolinium chloride (GD) or zymosan was injected intraperitoneally into rats and to endotoxin-resistant mice (C3H/HeJ). The animals were killed at different time points and their livers were immediately frozen in liquid nitrogen for RNA isolation and immunohistological studies. RNA was analyzed by real-time PCR and northern blot. Sera were used to measure transaminases, hepcidin and iron levels. The expression of iron metabolism genes, hepcidin, hemojuvelin (Hjv), ferroportin-1 (Fpn-1) and of the inflammatory cytokines IL-6, IL-1b, TNF-a and IFN-g was determined. Although phagocytosed material was detected in ED-1-and C1q-positive cells, no inflammatory cells were identified within the liver parenchyma. Serum levels of hepcidin, iron and transaminases did not differ from those of control animals. Both GD and zymosan induced an upregulation of hepcidin-gene expression in rat liver as early as 3 h, reaching a maximum 6 h after treatment. Hjv-and Fpn-1-gene expression was downregulated at the same time. IL-6 was by far the most induced acute-phase-cytokine in GD-and zymosan-treated livers, although IL-1b and TNF-a were also strongly upregulated by zymosan and to a lesser extent by GD. Similar results were obtained in the C3H/HeJ mouse strain excluding the possible role of contaminating endotoxin. This study shows that phagocytosis upregulates hepcidin-gene expression and downregulates Hjv-and Fpn-1-gene expression within the liver. These changes in iron-regulating-gene expression may be mediated by the locally produced acute-phase-cytokines.

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Section: Discussionsupporting

confidence: 80%

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi

Ahmad

Ramadori

et al. 2009

Laboratory Investigation

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“…Finally, FPN mRNA levels increase in bone marrow-derived macrophages following erythrophagocytosis and heme treatment, [11; 22; 23] as well as in Raw264.7 cells after hemoglobin supplementation [13]. Inflammatory stimuli, such as LPS [12], TNFα [24] and turpentine oil [15] can also regulate FPN mRNA levels, both in vivo and in vitro. In addition, it has been reported that high-altitude exposure is associated with an increase in skeletal muscle FPN mRNA levels in humans [14].…”

Section: Discussionmentioning

confidence: 99%

Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice

Chiabrando

Fiorito

Marro

et al. 2013

Blood Cells, Molecules, and Diseases

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Here we show that, during experimentally-induced acute anemia in mice, FPN is regulated at transcriptional level in a cell-specific manner. FPN mRNA level increases in duodenum and spleen macrophages, whereas it does not change in liver and is strongly down-regulated in erythroid precursors. These results were confirmed in Caco2 Raw264.7 and K562 cells treated with a hypoxic stimulus. Moreover, we found a differential expression of HIF1α and HIF2α in cells and tissues that might account for the specificity of FPN regulation.Thus, hypoxia, by directly controlling hepcidin and its target FPN, orchestrates a complex regulatory network aimed at ensuring rapid iron recovery from the periphery and efficient iron utilization in the erythroid compartment.

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“…However, changes in the expression of iron metabolism proteins in both hepatic and non-hepatic organs, including the brain, have been reported in a rat model of the acute-phase response (APR). 25,27,28 In addition, a significant increase in the hepatic content of iron has been reported in the rat model of turpentine oil (TO)-induced muscle damage. [25][26][27] In the present study, a reduction of the serum concentration associated with the increase in liver iron concentration ('sponge effect') is not paralleled by an increase in spleen iron concentration.…”

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confidence: 99%

“…However, this acute reduction of serum iron level is not only observed in cases of bacterial infections, but in all conditions associated with tissue damage, 24 as it has been reproduced in animal models. 25,26 The mechanisms governing hepatic iron metabolism under acute-phase conditions is poorly understood. However, changes in the expression of iron metabolism proteins in both hepatic and non-hepatic organs, including the brain, have been reported in a rat model of the acute-phase response (APR).…”

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Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

Naz

Malik

Sheikh

et al. 2012

Laboratory Investigation

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Liver is the central organ of iron metabolism. During acute-phase-response (APR), serum iron concentration rapidly decreases. The current study aimed to compare expression and localization of iron transport protein ferroportin-1 (Fpn-1) and of other iron import proteins after experimental tissue damage induced by injecting turpentine oil in the hind limbs of rats and mice. Serum and spleen iron concentration decreased with an increase in total liver, cytoplasmic and nuclear iron concentration. In liver, mRNA amount of Fpn-1, Fpn-1a, Fpn-1b, HFE, hemojuvelin (HJV) and hephaestin (heph) genes showed a rapid decrease. Hepcidin, divalent metal transporter-1 (DMT-1), transferrin (Tf) and Tf-receptor-1 (TfR1), TfR-2 (TfR2) gene expression was increased. Western blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2, and an increase in hepcidin was observed. Immunohistochemistry of DMT-1 and TfR2 were mainly detected in the nucleus of rat liver and spleen, whereas TfR1 was clearly localized in the plasma membrane. Fpn-1 was mostly found in the nuclei of liver cells, whereas in spleen, the protein was mainly detected in the cell membrane. Western blot analysis of liver fractions confirmed immunohistochemical results. In livers of wild-type mice, gene expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated, whereas hepcidin gene expression was increased. In contrast, these changes were less pronounced in IL-6ko-mice. Cytokine (IL-6, IL-1b and TNF-a) treatment of rat hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b, and upregulation of hepcidin gene expression. Moreover, western blot analysis of cell lysate of IL-6-treated hepatocytes detected, as expected, an increase of a2-macroglobulin (positive acute-phase protein), whereas albumin (negative acute-phase protein) and Fpn-1 were downregulated. Our results demonstrate that liver behaves as a 'sponge' for iron under acute-phase conditions, and Fpn-1 behaves as a negative acute-phase protein in rat hepatocytes mainly, but not exclusively, because of the effect of IL-6. These changes could explain iron retention in the cytoplasm and in the nucleus of hepatocytes during APR. The liver is the central organ for iron metabolism. 1 Liver cells (hepatocytes) take up iron absorbed from the diet, and Kupffer cells take up iron from aged erythrocytes and distribute it to different organs. Iron is an important co-factor for oxygen transport, heme and non-heme iron proteins, electron transfer, neurotransmitter synthesis, myelin production, energy metabolism and mitochondrial function, as well as for the production of reactive-oxygen species. 2,3 As a result, its metabolism is tightly regulated. Iron homeostasis is controlled by a large group of iron-regulatory proteins. The absorption of dietary iron begins with its transport across the duodenal brush-border membrane mediated by the duodenal metal transporter-1 (DMT-1), the major iron transporte...

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Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat

Cited by 84 publications

References 65 publications

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice

Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

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