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)

Bone marrow cells from patients with leukemia, myelodysplastic syndromes, cancer, and other disorders on a phase I clinical trial with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were assessed in vitro for numbers of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, and for growth patterns (colony-to-cluster ratio) of CFU-GM, cycling rates of CFU-GM, and responsiveness in vitro to colony-stimulating and colony-inhibiting factors. The colony-to-cluster ratio of CFU-GM and the dose-response curves of CFU-GM to stimulation by rhGM-CSF in vitro did not change during the clinical trial. However, the percentage of CFU-GM in DNA synthesis, which is a measure of the proliferative rates of these cells, determined by the high specific activity tritiated thymidine kill technique in vitro, was markedly enhanced in a reversible fashion after administration in vivo of rhGM-CSF. The increased cycling rates of CFU-GM were consistent with the induced increase in neutrophil counts in these patients that has been reported elsewhere. Additionally, marrow CFU-GM from patients given rhGM-CSF in vivo were increased in sensitivity to inhibition in vitro by recombinant human H-subunit (acidic) ferritin in two of eight cases, and were increased in sensitivity to inhibition by lower dosages of recombinant human tumor necrosis factor alpha in all patients evaluated. The sensitivity of CFU-GM to inhibition in vitro by recombinant human interferon gamma and prostaglandin E1 did not change during the clinical trial. These studies demonstrate that the rhGM-CSF is having an effect on CFU-GM in the patients on the phase I clinical trial. This information may be of significance in planning future clinical studies combining rhGM-CSF with chemotherapy and/or other biotherapy.
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PMID:Growth characteristics of marrow hematopoietic progenitor/precursor cells from patients on a phase I clinical trial with purified recombinant human granulocyte-macrophage colony-stimulating factor. 326 May 58

Recently, it was reported that nitric oxide (NO) directly controls intracellular iron metabolism by activating iron regulatory protein (IRP), a cytoplasmic protein that regulates ferritin translation. To determine whether intracellular iron levels themselves affect NO synthase (NOS), we studied the effect of iron on cytokine-inducible NOS activity and mRNA expression in the murine macrophage cell line J774A.1. We show here that NOS activity is decreased by about 50% in homogenates obtained from cells treated with interferon gamma plus lipopolysaccharide (IFN-gamma/LPS) in the presence of 50 microM ferric iron [Fe(3+)] as compared with extracts from cells treated with IFN-gamma/LPS alone. Conversely, addition of the iron chelator desferrioxamine (100 microM) at the time of stimulation with IFN-gamma/LPS increases NOS activity up to 2.5-fold in J774 cells. These effects of changing the cellular iron state cannot be attributed to a general alteration of the IFN-gamma/LPS signal, since IFN-gamma/LPS-mediated major histocompatibility complex class II antigen expression is unaffected. Furthermore, neither was the intracellular availability of the NOS cofactor tetrahydrobiopterin altered by treatment with Fe(3+) or desferrioxamine, nor do these compounds interfere with the activity of the hemoprotein NOS in vitro. We demonstrate that the mRNA levels for NOS are profoundly increased by treatment with desferrioxamine and reduced by Fe(3+). The half-life of NOS mRNA appeared not to be significantly altered by administration of ferric ion, and NOS mRNA stability was only slightly prolonged by desferrioxamine treatment. Nuclear run-off experiments demonstrate that nuclear transcription of cytokine-inducible NOS mRNA is strongly increased by desferrioxamine whereas it is decreased by Fe(3+). Thus, this transcriptional response appears to account quantitatively for the changes in enzyme activity. Our results suggest the existence of a regulatory loop between iron metabolism and the NO/NOS pathway.
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PMID:Iron regulates nitric oxide synthase activity by controlling nuclear transcription. 752 Apr 77

We have investigated the effects of the pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) on the iron metabolism of the human monocytic cell line U937. Cells were treated with each cytokine for up to 24 h, and then iron uptake from diferric transferrin was determined. The intracellular distribution of this iron, the expression of the transferrin receptor and levels of mRNA for the two ferritin subunits were also studied. IL-1 beta, TNF alpha and IFN gamma all decreased transferrin-iron uptake into cells, and all three cytokines had effects on the proportion of iron associated with ferritin. With TNF alpha there was a marked enhancement of the fraction incorporated into ferritin. Transferrin-receptor expression was diminished by TNF alpha and IL-1 beta, but not IFN gamma, suggesting different effector mechanisms. Both TNF alpha and IFN gamma increased the amount of cellular mRNA for ferritin H-chain, but not the L-chain; IL-1 beta affected mRNA for neither ferritin. These data demonstrate that cytokines, which can be present at high concentrations in inflammation, have the capacity to affect macrophage iron uptake, transferrin receptor expression, intracellular iron handling and the relative abundance of ferritin-subunit mRNA, and may therefore be important mediators in the observed perturbations of iron metabolism in inflammatory diseases.
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PMID:Modulation of iron metabolism in monocyte cell line U937 by inflammatory cytokines: changes in transferrin uptake, iron handling and ferritin mRNA. 825 Aug 40

Iron Regulatory Proteins (IRPs), by modulating expression of ferritin, which stores excess iron in a non toxic form, and transferrin receptor, which controls iron uptake, are the main controller of cellular iron metabolism. During inflammation, modification of IRP activity may affect iron availability, free radical generation and cytokine gene response in inflammatory cells. In the present study we tested the effect of inflammatory stimuli on IRP function in a human monocytic-macrophagic cell line and the possibility of interfering with these pathways by using an antiinflammatory compound, diacerhein (DAR). IRP activity was enhanced by interferon gamma/lipopolysaccarhide (IFN/LPS), and this effect was consistently counteracted by increasing concentrations of DAR. No direct effect of DAR on IRP activity was found in vitro. However, in vivo, similar IRP activation was achieved by exposing cells to nitric oxide (NO) donors and the LPS/IFN-induced activation of IRP was reversed by NO inhibitors. Interestingly, NO-induced IRP activation was efficiently blocked by DAR. These data show for the first time that a clinically useful antiinflammatory compound, DAR, interferes with IRP activation by NO in inflammed human cells.
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PMID:Diacerhein blocks iron regulatory protein activation in inflamed human monocytes. 977 19

After 2 years of steroid therapy that had effectively controlled her systemic lupus erythematosus, a 37-year-old woman presented with fever, erythema (face, upper chest), and low CH50. Increased oral steroid (prednisolone from 15 mg to 40 mg) and intravenous methylprednisolone (mPSL) (80 mg for 3 days) alleviated these symptoms except for the fever. Subsequently, the patient's fever worsened and leukocytopenia, abnormal liver function, lymphadenopathy (neck, axilla), and salivary gland swelling developed. Lymph node histology revealed features characteristic of Kikuchi-Fujimoto's disease (KFD). Laboratory examinations showed WBC 600/microliter, Hb 9.5 g/dl, platelets 90,000/microliter, GOT 766 IU/l, GPT 646 IU/l, LDH 4,228 IU/l, TG 1,622 mg/dl, and ferritin 6,330 ng/ml. Serum interferon gamma was also elevated (673 U/ml). Because a bone marrow smear revealed hemophagocytosis, mPSL pulse therapy (1 g for 3 days) was started for treatment of hemophagocytic syndrome. The fever promptly disappeared, and the patient's clinical symptoms resolved within 2 weeks. The abnormal laboratory data related to KFD and hemophagocytosis returned to normal within 4 weeks after the initiation of mPSL pulse therapy. We speculated that the hemophagocytosis and salivary gland involvement in this patient were also symptoms of KFD. This case indicated that corticosteroid pulse therapy is effective for KFD with serious clinical symptoms.
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PMID:[Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto's disease) accompanied by hemophagocytosis and salivary gland swelling in a patient with systemic lupus erythematosus]. 1069

Seven patients with peripheral B-cell lymphoma associated with hemophagocytic syndrome are reported. In all cases, the histologic subtype was diffuse large B-cell lymphoma. Hemophagocytic features were noted in the bone marrow with lymphomatous infiltration. Hemophagocytic syndrome occurred with presentation of the lymphoma and was characterized by high fever, cytopenias, and elevated levels of lactate dehydrogenase, ferritin, C-reactive protein, and cytokines [interferon gamma, macrophage colony-stimulating factor, soluble interleukin (sIL)-2R, and IL-6] without evidence of infection. The phenotypes of lymphomas were suspected CD19+, CD20+, S-Ig+, CD10-, and coexpression of CD5 in some cases. Flow cytometric analysis showed a low CD4/CD8 ratio in peripheral blood and bone marrow. We suggest that the pathogenesis of hemophagocytic syndrome is hypercytokinemia induced by a proliferation of reactive CD8+ T cells. Previous reports of B-cell lymphoma with hemophagocytic syndrome demonstrated similar clinical manifestations and poor prognoses. The invasion patterns of these diffuse large B-cell lymphomas with hemophagocytosis may be classified into three groups: microscopic lymph-node involvement type, gross lymph-node involvement type, and splenic lymphoma type. Although hemophagocytic syndromes have been reported to be associated with T-cell lymphomas, our results indicate an association with diffuse large B-cell lymphoma.
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PMID:B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. 1096 86

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

Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 confers protection against many types of cell and tissue damage by modulating apoptotic cell death or cytokine expression profiles, we hypothesized that adenovirus-mediated transfer of HO-1 cDNA and subsequent overexpression of the protein in lung would provide therapeutic benefit in a murine model of bleomycin-induced pulmonary fibrosis. In C57BL/6 mice, HO-1 overexpression clearly suppressed the development of fibrotic changes and was associated with enhanced interferon gamma production in lung and reduced numbers of respiratory epithelial cells with damaged DNA. However, HO-1 overexpression did not prevent pulmonary fibrosis induced by agonistic anti-Fas antibody inhalation in C57BL/6 or ICR mice, a strain known to develop pulmonary fibrosis via the Fas-Fas ligand (FasL) pathway. Consistent with the concept that HO-1 overexpression prevents fibrosis via a pathway independent of Fas-FasL interaction, Ad.HO-1 administration prevented bleomycin-induced pulmonary fibrosis in gld/gld mice, which express nonfunctional FasL. These observations suggest that using HO-1 overexpression strategies to treat idiopathic pulmonary fibrosis, or fibrotic disorders of other target organs, by attenuating apoptotic cell death likely would be effective in clinical situations.
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PMID:Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway. 1244

A 26-year-old woman presented with general fatigue, persistent fever, nuchal lymphadenitis, thrombocytopenia, and liver damage. From the bone marrow finding, we diagnosed her condition as hemophagocytic syndrome. Steroid pulse therapy, cyclosporin A treatment, and combined chemotherapy generated no response. The patient showed severe mucosal bleeding, rapidly experienced multiple organ failure, and finally died of a brain hemorrhage on the 13th hospital day. Epstein-Barr virus, cytomegalovirus, human herpes virus type 6, human parvovirus B19, and herpes simplex virus were not detected. Autopsied samples of the spleen, bone marrow, and liver showed extreme proliferation of activated macrophages, so-called histiocytes, without lymphoid malignancy. The interferon gamma level at presentation was prominently high. The continuously elevated levels of ferritin and soluble interleukin 2 receptor were correlated with the catastrophic outcome. The disease in our case mimicked infantile hemophagocytic lymphohistiocytosis. However, there was neither a family history of the disease nor a mutation in the perforin gene. So, it is reasonable to categorize our case as macrophage activation syndrome. Although our patient lacked arthritis or eruption, we cannot deny the possibility that an oligoarthritis type of systemic-onset juvenile rheumatoid arthritis or, considering the patient's age, adult-onset Still disease lies at the base of our case.
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PMID:Fulminant hemophagocytic syndrome with a high interferon gamma level diagnosed as macrophage activation syndrome. 1523 1

Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of inflammatory liver damage inducible by lipopolysaccharide (LPS) in mice sensitized with the hepatocyte-specific transcription inhibitor D-galactosamine (GalN). Our results show that HO-1 induction by cobalt-protoporphyrin-IX (CoPP) reduced cytokine expression, protected mice from liver injury, and prolonged survival. While in contrast to ferritin overexpression, single administration of the CO donor methylene chloride (MC) or of BV also protected mice from liver damage, only coadministration of both HO products prolonged survival and reduced the expression of cytokines, e.g., tumor necrosis factor (TNF) and interferon gamma (IFN-gamma). In conclusion, HO-1-induced prolongation of survival, but not the protection from liver damage, seems to be dependent on down-regulation of cytokine synthesis.
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PMID:Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury. 1572 11


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