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)

Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This suggests that TNF-alpha-induced synthesis of H-rich ferritin may reduce the regulatory pool of intracellular iron, secondarily inhibiting iron-mediated translation of ferritin mRNA. We conclude that TNF-alpha acts independently of iron in its induction of ferritin H mRNA but requires the presence of iron for this effect to be fully expressed at the protein level.
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PMID:Iron-independent induction of ferritin H chain by tumor necrosis factor. 205 77

Changes in transcription/accumulation of ferritin mRNA accompany cell differentiation and development as cells establish the pattern of iron storage and metabolism that matches their specialized features. Signals which induce changes in ferritin gene expression include hormones (thyrotropin in thyroid cells), monokines (tumor necrosis factor alpha in myoblasts, and preadipocytes), phagocytosis and/or inducing agents (erythrophagocytosis in macrophages, phorbol esters in promyelocytes, and dimethyslulfoxide in proerythroblasts), heat shock (in red cells) and light (in leaf mesophyll). Iron, which has a major effect on the translation of ferritin mRNA, also leads to synthesis and/or accumulation of ferritin mRNA in hepatocytes, adult red cells, HeLa cells, and undifferentiated plant cells. Iron-induced changes in ferritin mRNA composition allow cells to synthesize large amounts of different ferritins in response to excess iron. Whether iron will act both on translation and transcription may relate to the uses of stored iron by the cell (iron reserve for other cells? detoxification?) and the magnitude of the iron signal relative to the existing pool of ferritin mRNA. Translational regulation of ferritin mRNA depends on two distinctive features of the RNA: (1) conserved regulatory sequence of 28 nucleotides occurs in the 5' noncoding region (iron 'regulatory' or 'responsive' element, IRE) which interacts with cytoplasmic regulator proteins, present in animal cells, that block initiation; sequences in the 3' untranslated region can modulate translation when the IRE is present. (2) Ferritin mRNA, either deregulated by iron induction in cells or isolated from cells (polyA+), forms initiation complexes efficiently compared to other cellular mRNAs. The structure of the IRE, which is also found in the 3' untranslated region of the iron-destabilized transferrin receptor mRNA, has begun to be analyzed by computer prediction, site-directed mutagenesis, and solution behavior. The results to date show that the IRE is a hairpin with bulges and loops that is stacked upon a base-paired flanking region (FL) with varying sequence. Interactions of the IRE+FL with other parts of ferritin mRNA are indicated by comparing the reactivity of natural ferritin mRNA with an oligomer (n = 55). The structure of the stem nearest the hairpin loop is sequence-dependent and flexible. Variations in the distance of the IRE from the cap in various ferritin mRNAs, compensated by the length of FL, and the structural properties of the IRE+FL suggest that the 5' regulatory structure of ferritin mRNA includes the IRE+FL.
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PMID:Ferritin mRNA translation, structure, and gene transcription during development of animals and plants. 213 59

Interleukin 1 alpha (IL-1) and tumor necrosis factor alpha (TNF) are two monokines which play a prominent role in the response to inflammation and injury. We recently observed that TNF leads to an increase in the synthesis of the heavy chain of ferritin, suggesting that TNF may be involved in iron homeostasis (Torti et al. (1988) J. Biol. Chem. 263, 12638-12644). The experiments reported here demonstrate that in cultured human muscle cells, IL-1 induces ferritin H mRNA and protein as effectively as TNF. TNF and IL-1 were additive in their effects on ferritin H expression, and IL-1 induction of ferritin H was not blocked by anti-TNF antibodies. Ferritin H induction was a specific response not observed with beta or gamma interferon, nor with transforming growth factor beta. Both differentiated myotubes as well as myoblasts responded to IL-1 with the induction of ferritin H. These results suggest that monokine-mediated alterations in the subunit composition of the ferritin molecule may be of biological relevance in the response to inflammation and injury.
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PMID:Interleukin 1 induces ferritin heavy chain in human muscle cells. 235 Mar 50

Highly purified murine granulocyte-macrophage progenitor cells (CFU-GM) were used as target cells to assess the possible direct effects of purified preparations of recombinant murine gamma-interferon, prostaglandin E, recombinant human heavy chain (acidic) ferritin, and recombinant human tumor necrosis factor alpha (TNF-alpha) on progenitor cells in vitro. Target CFU-GM, with cloning efficiencies of up to 84% and containing 0-3% morphologically recognizable accessory cells at the initiation of the culture period, were plated at a density of 100-150 cells/dish in the presence or absence of pure suppressor molecules. Colony formation was stimulated with either crude pokeweed mitogen-stimulated mouse spleen conditioned medium, pure natural murine macrophage colony-stimulating factor, or pure recombinant murine granulocyte-macrophage colony-stimulating factor. All four suppressor molecules were active in vitro against purified CFU-GM as assessed by their ability to inhibit colony or cluster formation. No apparent difference in the degree of responsiveness to prostaglandin E, gamma-interferon, or human heavy chain (acidic) ferritin was noted in the presence of pokeweed mitogen-stimulated mouse spleen conditioned medium, granulocyte-macrophage colony-stimulating factor, or macrophage colony-stimulating factor. In contrast, TNF-alpha in cultures containing macrophage colony-stimulating factor slightly, but significantly, potentiated colony formation. TNF-alpha also appeared more active at suppressing colony formation at lower concentrations in pokeweed mitogen-stimulated mouse spleen conditioned medium than in granulocyte-macrophage colony-stimulating factor-stimulated cultures of purified CFU-GM. The results suggest that TNF-alpha, human heavy chain (acidic) ferritin, gamma-interferon, and prostaglandin E can act directly at the progenitor cell level.
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PMID:Effects of hematopoietic suppressor molecules on the in vitro proliferation of purified murine granulocyte-macrophage progenitor cells. 244 53

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

Anaemia of chronic disease is that associated with inflammatory disorders such as prolonged infections, auto-immune diseases and some cancers. The pathogenesis of anaemia of chronic disease is complex and includes a reduced erythropoiesis, slightly shortened red cell survival, and changes in the iron metabolism. New experimental data have shown that cytokines released during the inflammatory process are of crucial importance in this context. In particular interleukin-1 and tumor necrosis factor alpha, released from activated macrophages, have been shown to inhibit erythropoiesis and might initiate changes in iron metabolism. Clinically, anaemia of chronic disease is mild and the underlying disease usually dominates the clinical picture. Most often, the anaemia takes the form of a normocytic, normochromic anaemia with low serum iron although the iron stores are normal or increased. Anaemia of chronic disease should be distinguished from anaemia due to iron deficiency, and at the moment measurement of serum ferritin seems to be the best analysis for this purpose.
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PMID:[Anemia in chronic disease]. 806 33

To define the toxicity profile of recombinant human interleukin-6 (rhIL-6) and to study its effect on hematopoiesis, biochemical parameters and other cytokines, rhIL-6 was administered in a phase I-II study to 20 patients with breast carcinoma or nonsmall cell lung cancer. RhIL-6 doses were 0.5, 1.0, 2.5, 5.0, 10, and 20 micrograms/kg/d, with at least three patients per dose level. RhIL-6 was administered 24 hours by continuous intravenous infusion followed by subcutaneous (SC) administration for 6 days, partly on an outpatient basis. RhIL-6-related side effects were fever, headache, myalgia, and local erythema. Starting at 2.5 micrograms/kg/d, these side effects were compounded by nausea, reversible increase in liver enzymes, and anemia. Flu-like symptoms were controllable up to and including 10 micrograms rhIL-6/kg/d with acetaminophen. RhIL-6 increased platelet counts with a decrease in mean platelet volume and increased leukocytes caused by neutrophil, monocyte, and lymphocyte increase, with an increase in T cells and natural killer cells at 1.0 and 2.5 micrograms rhIL-6/kg/d. The reversible anemia was characterized by a decrease in serum iron, and an increase in ferritin and erythropoietin without reticulocytosis. RhIL-6 reduced total cholesterol levels and a dose-related increase of C-reactive protein and serum amyloid A plasma levels was observed. Serum IL-6 levels were increased, especially at 10 and 20 micrograms/kg/d, whereas no change in IL-1 beta and tumor necrosis factor alpha levels was observed. RhIL-6 can be administered with controllable side effects in this setting, up to and including a SC dose of 10 micrograms/kg/d on an outpatient basis, and has a promising stimulating effect on leukopoiesis and thrombopoiesis.
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PMID:Effects of recombinant human interleukin-6 in cancer patients: a phase I-II study. 806 39

We describe a rare case of pleomorphic type of malignant fibrous histiocytoma (MFH) in the buttock that presented a systemic involvement. The case was of a 58-year-old woman presenting hepatic dysfunction and inflammatory reactions including fever, positive C-reactive protein (CRP), an elevated erythrocyte sedimentation rate, and high levels of platelets and ferritin. The fever of 3 months duration subsided on the first postoperative day. The MFH resection also brought rapid normalization in CRP, platelets, and leukocytes. The local and systemic productions of cytokines induced by this tumor were evaluated. In vivo and in vitro production of interleukin (IL)-6, IL-1beta, and tumor necrosis factor alpha by tumor cells were measured using enzyme-linked immunosorbent assay. Blood samples taken preoperatively, tumor tissues, and the primary culture medium showed extraordinarily high IL-6 levels. The plasma IL-6 level was normalized postoperatively. Immunohistochemistry showed the positivity of tumor cells for IL-6. The IL-6 produced by the tumor was concluded to have been responsible for the systemic illness.
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PMID:IL-6 in a pleomorphic type of malignant fibrous histiocytoma presenting high fever. 967 Aug 36

Sepsis is often associated with a downward spiral through a spectrum of systemic inflammatory response syndrome (SIRS) culminating in organ failure and death. Here we present a 3-year-old girl with Hemophilus influenzae septic meningitis who developed SIRS and acute renal failure. In the initial stage, the patient showed uremia, cytopenia, disseminated intravascular coagulation, elevation of tissue enzyme and ferritin values, hemophagocytosis and overproduction of nitric oxide. The serum cytokine profile revealed increased levels of soluble interleukin (IL)-2 receptor, IL-6, IL-10 and tumor necrosis factor alpha. The patient responded positively to early and intensive interventions including antibiotics, repeated exchange transfusions, dexamethasone and high-dose gamma-globulin. The above laboratory abnormalities almost normalized with clinical improvement. We consider that SIRS was probably responsible for the sequence of events resulting in renal failure in this case, and suggest that renal failure should be included among the serious complications of SIRS associated with Hemophilus influenzae septic meningitis.
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PMID:Systemic inflammatory response syndrome and acute renal failure associated with Hemophilus influenzae septic meningitis. 1087 2

Echinacea extracts are widely used in European countries and in the United States as "immune-stimulating" agents. Even though the evidence to stimulate certain components of the nonspecific immune system (phagocytosis, macrophages, and production of cytokines) stems from in vitro experiments or studies after parenteral application, the commercially available Echinacea preparations used as drugs or supplements are for oral use. The aim of the study was to determine whether phagocytic activity and production of cytokines is stimulated by oral application of a commercially available Echinacea preparation. Forty healthy male volunteers (ages 20-40 years) participated in the study. They received either a freshly expressed juice of Echinacea purpurea herbs or placebo juice using a double-blind placebo-controlled crossover design with two treatment periods of 14 days and a wash-out period of 4 weeks in between. Endpoints for immune stimulation: phagocytic activity of polymorphonuclear leukocytes and monocytes measured by flowcytometry, production of tumor necrosis factor alpha (TNF)-alpha and Interleukin (IL)-1beta by LPS-stimulated blood monocytes. Echinacea purpurea herbs did neither enhance phagocytic activity of polymorphonuclear leukocytes nor that of monocytes when compared with placebo. Echinacea purpurea herbs did not influence the production TNF-alpha and IL-1beta by LPS-stimulated monocytes. Unexpectedly, Echinacea purpurea herbs decreased serum ferritin concentration (p = 0.0005). All other laboratory and safety data remained unchanged. The "immune stimulation" by Echinacea purpurea observed in vitro and after parenteral administration are not confirmed in healthy humans after oral intake. Other immunomodulatory effects may explain the benefits of Echinacea preparations in reducing duration and severity of upper-respiratory tract infections found in randomized, double-blind clinical trials.
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PMID:Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men: results of a double-blind, placebo-controlled crossover study. 1221 79


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