Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This investigation demonstrates that low concentrations (25 microM) of free and transferrin-bound iron reduce the efficiency of the interferon-gamma (IFN-gamma) signal in the human myelomonocytic cell line THP-1, as seen by decreased production of neopterin, reduced degradation of tryptophan, and impaired expression of major histocompatibility complex (MHC) class II antigens. This inhibitory effect of iron, which is not due to an enhanced cytotoxicity towards THP-1 cells, is increased by enhancement of iron concentrations in a dose-dependent relationship and can be partially reversed by increasing amounts of the cytokine. The iron-mediated inhibition of the effects of IFN-gamma is fully reversed when iron is administered concomitantly with equimolar concentrations of the iron chelator deferoxamine. Furthermore, deferoxamine alone is even able to enhance the efficiency of the IFN-gamma signal. Our data provide evidence that there is an inverse correlation between the intracellular amount of iron, which is not bound to ferritin, and the activity of the IFN-gamma signal. This suggests that iron withholding by the immune cells in the course of inflammatory disorders may also contribute to the enhancement of the cytopathic effect of IFN-gamma. This speculation is confirmed by the observation of high concentrations of immune activation markers such as IFN-gamma and neopterin and low serum iron levels in patients with hypoferric anemia in the course of chronic inflammation.
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PMID:Iron modulates interferon-gamma effects in the human myelomonocytic cell line THP-1. 158 6

To identify genes potentially implicated in atherogenesis, a cDNA library was constructed from human atherosclerotic aorta and differentially screened with 32P-labeled-cDNAs prepared from human normal and atherosclerotic aortas. Two cDNA clones exhibiting higher hybridization to the 32P-labeled cDNAs from atherosclerotic vessels were isolated and identified to be genes encoding L-ferritin and H-ferritin, respectively. Northern blot analysis confirmed that the expression of both ferritin genes was notably higher in human and rabbit atherosclerotic aortas than in their normal counterparts. A time-course study illustrated that both L- and H-ferritin mRNAs were markedly increased in aortas of rabbits after feeding with a high cholesterol diet for 6 wk, which was also the time period after which the formation of lesions became evident. In situ hybridization revealed that both L- and H-ferritin mRNAs were induced in endothelial cells and macrophages of human early lesions. The signals were also detected in the smooth muscle cells of advanced lesions. Immunostaining further identified the presence of ferritin protein in atherosclerotic lesions. On the other hand, Prussian blue stain revealed the presence of iron deposits in advanced lesions but not in early human or rabbit lesions. Further experiments with cultured human monocytic THP-1 cells and aortic smooth muscle cells demonstrated that ferritin mRNAs were subjected to up-regulation by treatment with IL-1 or TNF, while TGF, PDGF, and oxidized LDL did not affect the expression of either ferritin gene in both cell lines. Collectively, these results clearly demonstrate that ferritin genes are susceptible to induction in the course of plaque formation.
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PMID:Increased ferritin gene expression in atherosclerotic lesions. 863 99

The mRNA coding for H-ferritin was highly induced in human monocytic THP-1 cells following treatment with phorbol 12-myristate 13-acetate (PMA). The induction was detected at 3 h, reached maximal levels at 12 h, and was sustained for up to 48 h subsequent to PMA exposure. PMA-induced up-regulation of H-ferritin gene expression was also observed in other leukaemic cell lines, HL60 and U937, but not in non-leukaemic cell types, including human fibroblasts, endothelial cells and smooth muscle cells. The effect of PMA could be completely blocked by the protein kinase C inhibitor, H-7. Furthermore, treatment of THP-1 cells with bacterial phospholipase C also produced a marked increase in expression of H-ferritin mRNA, suggesting the activation of protein kinase C was responsible for the accumulation of mRNA. Nuclear run-off experiments demonstrated that PMA did not increase the transcriptional rate of the H-ferritin gene. In contrast, the half-life of the H-ferritin mRNA measured in the presence of actinomycin D was greatly prolonged in PMA-treated cells. The induction of H-ferritin mRNA by PMA required no protein synthesis. Conversely, treatment of THP-J cells with protein synthesis inhibitor, cycloheximide, resulted in a 4-5-fold increase in H-ferritin mRNA. The increase in the stability of the H-ferritin mRNA was also observed in cells treated with cycloheximide. Taken together, these results suggest that the stability of H-ferritin mRNA in THP-1 is subjected to regulation via a protein kinase C-mediated phosphorylation on existing putative protein factor(s).
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PMID:Post-transcriptional regulation of H-ferritin gene expression in human monocytic THP-1 cells by protein kinase C. 887 Jun 67

The acute-phase protein alpha 1-antitrypsin (alpha 1-AT) has been shown to inhibit the binding of transferrin to its cell-surface receptor. Here we demonstrate that in human erythroleukaemic cells (K562) alpha 1-AT enhances the binding affinity of iron-regulatory protein (IRP), the central regulator of cellular iron metabolism, to iron-responsive elements. Activation of IRP by alpha 1-AT is associated with a marked increase in transferrin receptor (trf-rec) mRNA levels in K562 and enhanced cell-surface expression of transferrin-binding sites, whereas ferritin production is decreased, although ferritin mRNA levels remain unchanged. In agreement with the well-established mechanism of cellular iron regulation, alpha 1-AT seems to modulate trf-rec and ferritin expression primarily post-transcriptionally/translationally by influencing IRP activity. In contrast, alpha 1-AT produces only minor changes in IRP activity, and subsequently in trf-rec expression and ferritin synthesis in THP-1 cells. Moreover the effects of alpha 1-AT on iron homeostasis in K562 cannot be overcome by the addition of iron salts, whereas concomitant treatment of THP-1 with iron and alpha 1-AT results in the same metabolic changes as the addition of iron alone. Because alpha 1-AT blocks transferrin binding on K562 as well as on THP-1 cells, it is suggested, on the basis of the results presented here, (1) that erythroid and monocytic cells might differ in their dependence on transferrin-mediated iron supply and (2) that THP-1 might be able to acquire iron by a transferrin-independent iron uptake system. alpha 1-AT might therefore be involved in the diversion of iron traffic between various cellular compartments under inflammatory conditions.
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PMID:Divergent effects of alpha 1-antitrypsin on the regulation of iron metabolism in human erythroleukaemic (K562) and myelomonocytic (THP-1) cells. 892 Sep 96

To identify the host genes induced or suppressed by infection of mycobacteria, the reverse transcriptase polymerase chain reaction (RT-PCR) and the differential display reverse transcriptase polymerase chain reaction (DD RT-PCR) methods were used. In this study, cDNAs complement to mRNA extracted from human peripheral monocyte derived naive THP-1 cells, THP-1 cells infected with live Mycobacterium bovis BCG, THP-1 cells treated with heat-killed BCG, and THP-1 cells incubated with IgG-coated glass-beads were compared on the sequencing gel. One (TG2-1) of the clones selected by DD RT-PCR is 446 bp long and is identical to human ferritin heavy (H) chain gene. Northern blot analysis confirmed that ferritin H chain gene has been markedly over-expressed in monocytic THP-1 cells incubated with live and dead M. bovis BCG. Differential display techniques of host genes whose expression levels were varied by infection of mycobacteria could provide information about the response of macrophages to mycobacterial infection.
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PMID:Differential expression of ferritin heavy chain in THP-1 cells infected with Mycobacterium bovis BCG. 941 6

The reticuloendothelial (RE) system plays an important role in the changes in iron metabolism associated with the anemia of chronic disease (ACD). We previously reported that the acute-phase protein alpha1-antitrypsin (alpha1-AT) reduced growth and proliferation in cells of the erythroid cell system by interfering with transferrin (Tf)-mediated iron uptake. The regulation of iron metabolism in cells of the RE system is distinctly different from that in other cell systems; moreover, monocytes and macrophages play an essential part in the regulation of the production and clearance of alpha1-AT. In the present study we examined the effect of alpha1-AT on cells of the monocyte-macrophage lineage. Alpha1-AT completely inhibited the binding of Tf to its receptor (TfR) on THP-1 human myelomonocytic cells and cultured human monocytes. Results of equilibrium saturation and kinetic studies indicated that this inhibition was competitive. No other acute-phase protein demonstrated the same inhibitory potency. Furthermore, alpha1-AT almost completely prevented internalization of the Tf-TfR complex in a dose-dependent manner. Interestingly, and in sharp contrast to the results of our studies with erythroid cells, this inhibition did not reduce the growth and proliferation of THP-1 cells. Furthermore, alpha1-AT significantly increased the concentration of intracellular ferritin in THP-1 cells and monocytes, whereas the number of TfR remained unchanged. Because alpha1-AT showed no enhancing effect on ferritin transcription and translation, we believe that an as-yet unidentified posttranslational mechanism may be responsible for this phenomenon. In addition, our results indicate that the increase in ferritin concentration caused by alpha1-AT is mediated independently of iron supply, as has previously been shown for several proinflammatory cytokines. These data provide further evidence that alpha1-AT is a mediator of the alterations in iron metabolism characteristic of ACD.
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PMID:Modulation of iron metabolism in monocytic THP-1 cells and cultured human monocytes by the acute-phase protein alpha1-antitrypsin. 976 45

We have previously demonstrated that phorbol myristate acetate (PMA) up-regulates H-ferritin gene expression in myeloid cells by stabilization of its message. In the present report, we showed that insertion of the 3'-untranslated region (3'-UTR) of H-ferritin mRNA at the 3'-end of luciferase coding sequence significantly reduced the stability of luciferase mRNA in human monocytic THP-1 cells. However, the half-life of the chimeric transcript was markedly prolonged after PMA treatment. A cytosolic protein factor from THP-1 cells was found to specifically bind to H-ferritin 3'-UTR. PMA treatment of THP-1 cells resulted in the reduction of the RNA binding activity in a time-dependent manner. Deletion analysis and RNase T1 mapping revealed a pyrimidine-rich sequence within the 3'-UTR which interacts with the protein factor. Competition experiments with homoribopolymers further demonstrated the importance of uridines for the binding activity. Point mutations in uridines of the pyrimidine-rich sequence reduced the protein binding to 3'-UTR, while increasing the stability of the chimeric luciferase transcript. Together, these results demonstrate that the pyrimidine-rich sequence in the 3'-UTR is involved in post-transcriptional regulation of H-ferritin gene expression in myeloid cells.
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PMID:Post-transcriptional regulation of H-ferritin mRNA. Identification of a pyrimidine-rich sequence in the 3'-untranslated region associated with message stability in human monocytic THP-1 cells. 1051 12

Genes induced or suppressed by oxidized low-density lipoproteins (oxLDL) in human monocytic THP-1 cells were searched using differential display reverse transcriptase polymerase chain reactions (DDRT-PCR). Among the many differentially expressed cDNA fragments, one was dramatically stimulated by the oxLDL in a steady state level, which was later found to contain sequences corresponding to ferritin light chain (L-ferritin) in a sequence homology search. The stimulatory effect of the oxLDL on the level of L-ferritin mRNA in the THP-1 cells was both time- and dose-dependent. When the cells were allowed to differentiate in the presence of phorbol 12-myristate 13-acetate (PMA), the differentiated cells were generally less responsive to the oxLDL than the undifferentiated ones. An increase of L-ferritin mRNA was observed when the cells were treated with the lipid components in the oxLDL such as 9-HODE, 13-HODE, and 25-hydroxycholesterol. In addition, a stimulation of the L-ferritin gene expression was also observed when the cells were treated with an endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, 15d-PGJ2, in a time- and dose-dependent manner. These results suggest that oxLDL or its constituents are related to the stimulation of L-ferritin expression via PPARgamma.
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PMID:Regulation of ferritin light chain gene expression by oxidized low-density lipoproteins in human monocytic THP-1 cells. 1055 12

Few human monoblastic cell lines have been characterized to date. We have established the SigM5 cell line from a patient with acute monoblastic leukaemia (FAB M5a). Original leukaemic cells had a karyotype of 47,XY,+8, whereas the cell line showed a stemline clone of 81,XX,Y,Y,1,4,6,7,+8,+8,9,10,10,11,13,16,19[cp], with a minor sideline also present. Cytochemical staining was strongly positive with alpha-naphthylbutyrate acetate esterase, particulate positive with Sudan black and weakly positive for myeloperoxidase. Cells were positive for CD13, CD15, CD18, CD23, CD33, CD38, CD45, CD68 and myeloperoxidase. CD14 expression was 3-15%. SigM5 constitutively secreted interleukin (IL)-2, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, ferritin, lysozyme, N-elastase and neopterin upon stimulation with interferon (IFN)-gamma. Cells expressed the proinflammatory mediator macrophage migration inhibitory factor (MIF). All NADPH oxidase subunits were constitutively present, but nitroblue tetrazolium reduction was only detectable upon activation with IFN-gamma. SigM5 monoblasts were sensitive to arsenic trioxide (As2O3) previously not described to induce apoptosis in monoblastic cells. Differing considerably in morphology, immunophenotype and sensitivity to arsenics from the widely used cell lines U937, HL-60 and THP-1, SigM5 is a new monoblastic cell line useful for studying leukaemogenesis, monocyte differentiation and tumour cell susceptibility to arsenic compounds.
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PMID:Establishment and characterization of an arsenic-sensitive monoblastic leukaemia cell line (SigM5). 1084 31

The human monocytic cell line THP-1 differentiates along the macrophage line after phorbol-12-myristate-13-acetate (PMA) supplementation and can be stimulated to secrete tumour necrosis factor alpha (TNF-alpha) by interferon gamma (IFN-gamma) addition. We found that, in the early stage of differentiation (1-48 h), PMA induction elicited an upregulation of intracellular H ferritin and H ferritin binding sites and a downregulation of transferrin receptor. In addition, we found that iron administration to PMA-differentiating cells induced the expression of TNF-alpha mRNA and TNF-alpha secretion to levels even higher than those induced by IFN-gamma alone. The iron chelator desferrioxamine showed the opposite effect and reduced TNF-alpha release. In contrast, preincubation of the cells with iron before PMA induction resulted in a decrease of the TNF-alpha secretion induced by IFN-gamma, whereas the opposite was true after preincubation with desferrioxamine. The data support a co-ordinate interaction between iron and TNF-alpha in monocyte macrophages, with an iron-mediated upregulation of TNF-alpha in the early phase of differentiation and an iron-mediated inhibition at later stages. This complex relationship has to be considered in evaluating the effects of iron on inflammation.
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PMID:Relationship between TNF-alpha and iron metabolism in differentiating human monocytic THP-1 cells. 1105 92


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