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

To examine RNA/protein synthesis of neutrophils and related dynamic changes during the inflammatory process, we investigated mRNA expressions in neutrophils, by RNA blot hybridization analyses using 12 different rabbit gene probes. We first selected five candidate genes encoding inflammation-related proteins, i.e. tumor necrosis factor (TNF-alpha) IL-1 alpha, IL-1 beta, neutrophil activating peptide-1/IL-8 (NAP-1/IL-8) and monocyte chemoattractant protein (MCP)-1. We further selected several genes on basis of the results from gene subtraction between cDNA libraries from neutrophils at an early (5 h) and at a late (24 h) stage of casein-induced acute peritonitis in rabbits, i.e. immune activation gene-2 (Act-2), migration inhibitory factor-related protein-8 (MRP-8), MRP-14, gamma-actin, and formyl-methionyl-leucyl-phenylalanine receptor (fMLP-R), and ferritin light (L) chain. In addition to these genes we used ferritin heavy (H) chain gene, another component of the ferritin molecule. We examined mRNA expressions by cytoplasmic slot blot analysis of the above 12 genes in neutrophils obtained from blood and from various stages of casein-induced inflammation in rabbits. The observed patterns of mRNA expression kinetics were classified into three. Pattern 1: mRNAs of MRP-8, MRP-14, and gamma-actin were constitutively expressed in blood neutrophils, and increased rapidly after emigration into inflammatory sites. Pattern 2: mRNAs of IL-1 beta, NAP-1/IL-8, Act-2, and fMLP-R were undetectable in blood neutrophils, and were induced rapidly after the onset of inflammation. Pattern 3 mRNAs of ferritin L and H chain were induced slowly, and increased with progression of the inflammatory process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dynamic changes in mRNA expression of neutrophils during the course of acute inflammation in rabbits. 814 23

Inflammatory low iron is the second cause, after true iron deficiency, of acquired anaemia. It is mainly due to insufficient erythropoiesis resulting from inhibition of the erythroid progenitor and to disturbances in the synthesis and action of erythropoietin. These changes seem to be dependent on factors, such as TNF-alpha, interleukin-1 and interferon-gamma, which are released in inflammatory processes. Alterations in iron metabolism seem to be secondary, but also partly provoked by the same inhibitory agents. All these anaemias share a common character, i.e. lowering of serum iron level without increase of transferrin level, while plasma ferritin level is within normal limits. In addition to symptomatic therapy by red cell transfusions, numerous trials have shown that recombinant erythropoietin is effective in the treatment of the anaemia that accompanies cancers, chronic inflammatory and rheumatic diseases and of the anaemia provoked by HIV infection.
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PMID:[Inflammatory hyposideremic anemia]. 823 81

Peptide-specific IgG from a rabbit immunized with an alanine-lysine-proline-arginine ((ALA1)-tuftsin) containing 14-mer "ferritin" peptide neutralized rat liver ferritin inhibition of in vitro CSF-1-dependent monocytopoiesis. Antiferritin IgG similarly neutralized the inhibitory effect of ferritin but did not neutralize peptide inhibition of the in vitro myelopoietic response. No cross-reactivity between the respective antibodies and Ag was detected either by Western immunoblot or by competitive ELISA. Depletion of adherent cells before marrow cell culture significantly reduced the inhibitory effect of ferritin but did not influence peptide inhibition of CSF-1-stimulated colony formation. Adherent marrow cells and P388D1 cells treated with both CSF-1 and ferritin, but not either alone, produced inhibitory supernatant culture media that were neutralized by antipeptide but not antiferritin IgG. High resolution molecular sieve chromatography of the inhibitory adherent marrow cell and P388D1 supernatants resolved two peaks of 50 to 60 kDa and approximately 30 kDa in each. The inhibitory activity in all four peaks was neutralized by antipeptide but not antiferritin IgG. The ferritin/CSF inhibitors were not further characterized although identity with IL-6, IL-8, TNF-alpha, transforming growth factor-beta, and IFN-alpha/beta could be eliminated. The results indicate that ferritin inhibition of CSF-1-dependent monocytopoiesis is mediated by an endogenously produced inhibitor, or inhibitors, that shares antigenic similarity with the (ALA1)-tuftsin-containing 14-mer peptide and that adherent marrow cells, most likely monocytes or macrophages, produce the endogenous inhibitors in response to both CSF-1 and ferritin.
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PMID:Cytokine mediation of the suppressive effect of ferritin on colony-stimulating factor-1-dependent monocytopoiesis. 849 5

The present report describes the value of the plasma determination of TNF-alpha, at diagnosis, in 43 patients with non-Hodgkin's lymphoma (NHL), related to their clinical presentation and the new International Prognosis Index (IPI). We also compare the levels of TNF-alpha with those of LDH, beta-2-microglobulin (beta-2-m), and ferritin. At diagnosis, the mean values of the quotients between the marker values and the maximum value of normal (ratio:r-) are placed 7 times higher than normal for r-TNF-alpha, whereas those of r-beta-2-m and r-LDH are 2,4 and 1,4 times more respectively. We found a relationship between the value of r-TNF-alpha and the ECOG, Ann Arbor stage, the number of affected extranodal sites, and between the values of r-beta-2-m with r-LDH. The best correlation was obtained between the values of r-TNF-alpha and r-beta-2-m and IPI, however r-TNF-alpha best stratify the four risk groups in this prognosis index.
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PMID:Value of the determination of TNF-alpha in the plasma of patients with non-Hodgkins lymphoma. 883 7

The dependence of intestinal epithelial cell (IEC) growth and differentiation on intraepithelial lymphocytes (IELs) expressing the gamma/delta (gamma delta) T-cell receptor (TCR), suggested a potential role for gamma delta + IELs in the regulation of iron absorption. We therefore examined the levels of hepatic iron and the IEL cytokine responses in C57BL/6J control and class I and TCR knockout lines (placed on a C57BL/6J genetic background) following the administration of supplemental dietary iron. The highest level of liver iron was found in the beta 2-microglobulin knockout (beta 2m-/-) mice followed by the TCR-delta knockout (TCR delta-/-) animals. TCR-alpha knockout (TCR alpha-/-) and control animals did not differ in their iron levels. Liver iron loading correlated inversely with the ability of the mice to generate an IEL tumor necrosis factor (TNF)-alpha response. These observations suggest a model in which IEC iron loading is communicated to IELs via the HFE class I protein. The result of this communication is the initiation of TNF-alpha release by gamma delta + IELs (sustained by macrophages and dendritic cells) contributing to the upregulation of ferritin expression and possibly to the normal maintenance of the IEC apoptotic pathway.
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PMID:Gamma delta intraepithelial lymphocytes drive tumor necrosis factor-alpha responsiveness to intestinal iron challenge: relevance to hemochromatosis. 1031 64

Extracellular iron, which is predominantly bound by transferrin, is present in low concentrations within alveolar structures, and concentrations are increased in various pulmonary disorders. Iron accumulation by cells can promote oxidative injury. However, the synthesis of ferritin stimulated by metal exposure for intracellular iron storage is normally protective. The cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta may alter iron metabolism by alveolar cells. In this study, we assessed the effects of TNF-alpha and IL-1beta on iron metabolism with a cell line with properties of type 2 alveolar epithelial cells (A549) exposed to non-transferrin-bound (NTBI; FeSO(4)) or transferrin-bound (TBI) iron. In addition, we assessed the cytotoxicity of these exposures by measuring the cell accumulation of malondialdehyde (MDA), a product of lipid peroxidation, and cell death (MTT assay and lactate dehydrogenase release). A549 cells treated with NTBI or TBI in concentrations up to 40 microM accumulated iron and synthesized predominantly L-type ferritin without accumulation of MDA or cell death. Treatment of A549 cells with TNF-alpha (20 ng) or IL-1beta (20 ng) decreased cell transferrin-receptor expression and induced synthesis of H-type ferritin. TNF-alpha and IL-1beta decreased the uptake of TBI; however, the uptake of NTBI was increased. Both cytokines enhanced total ferritin synthesis (H plus L types) in response to iron treatments due to enhanced synthesis of H-type ferritin. Coexposure to TNF-alpha and NTBI, but not to TBI, induced MDA accumulation and greater cytotoxicity (MTT and lactate dehydrogenase release) than TNF-alpha alone. These findings indicate that TNF-alpha and IL-1beta modulate iron uptake by A549 cells, with differing effects on TBI and NTBI, as well as on H-ferritin synthesis. Enhanced iron uptake induced by TNF-alpha and NTBI was also associated with increased cytotoxicity to A549 cells.
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PMID:Effects of TNF-alpha and IL-1beta on iron metabolism by A549 cells and influence on cytotoxicity. 1044 19

Reactive oxygen species may contribute to airway injury in patients with cystic fibrosis (CF) and iron catalyzes oxidant injury by promoting generation of highly reactive hydroxyl radicals. Iron in the lower respiratory tract may be free, ferritin bound (from which iron can be reductively mobilized), or transferrin bound (which generally prevents iron mobilization). Ferritin is composed of subunits that are heavy (H) or light (L), and H-rich ferritins have additional biologic effects including inhibition of lymphocyte proliferation and cell growth. To assess concentrations of iron and iron-binding proteins in the lower respiratory tract of patients with CF, we measured iron (ferrozine), L-ferritin, H-ferritin, and transferrin (enzyme-linked immunosorbent assay [ELISA]) in bronchoalveolar lavage (BAL) fluid recovered from stable patients with CF (n = 8), healthy nonsmokers (NS; n = 8), or heavy cigarette smokers (HS; n = 8). Iron was detected in BAL fluid from patients with CF and HS, but not NS, with higher iron concentrations in patients with CF (42.0 +/- 11.6 microgram/dl) than in HS (9.9 +/- 2.6 microgram/dl, p < 0.05). Ferritin was present in all BAL fluids, with higher total ferritin (L + H) in patients with CF (647 +/- 84 ng/ml) than in HS (181 +/- 25 ng/ml, p < 0.005) or NS (9 +/- 3 ng/ml, p < 0.0005). Ferritin recovered from HS and NS lungs was < 2% H type, whereas ferritin in CF lungs was > 40% H-type ferritin. Transferrin concentrations in BAL fluid were not different in any group. Tumor necrosis factor (TNF)-alpha was present only in BAL samples from patients with CF. To assess whether TNF-alpha contributed to H-ferritin accumulation in CF lungs, we treated lung epithelial cells (A549) with iron alone (FeSO(4), 10-40 microM) or with iron and TNF-alpha (5-20 ng/ml). Iron-treated A549 cells synthesized almost entirely L-ferritin whereas exposure to TNF-alpha with iron caused a dose-dependent increase in accumulation of H-type ferritin. These findings suggest that oxidant injury could be promoted in lungs of patients with cystic fibrosis by iron mobilized from extracellular ferritin and, in addition, that TNF-alpha-promoted accumulation of H-type ferritin may impair local immune function and cell growth.
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PMID:Increased concentrations of iron and isoferritins in the lower respiratory tract of patients with stable cystic fibrosis. 1047 99

Our objectives were to study the value of different proteins in the serum and ascitic fluid and assess their potential in discriminating between malignant and nonmalignant ascites in a model that could be developed to aid clinical diagnosis. In all, 57 different measurements (30 in serum and 27 in ascitic fluid) including erythrocyte sedimentation rate, number of white blood cells, cytokines, interleukin-1a (IL-1a), IL-1b, IL-2, IL-6, IL-8, tumor necrosis factor-alpha, immunoglobulins (IgG, IgA, IgM), complement factors C3 and C4, acute-phase proteins such as alpha1-acid glycoprotein, alpha2-macroglobulin, alpha1-antitrypsin, haptoglobin, C-reactive protein, ferritin, ceruloplasmin and transferin, were performed in 61 patients with ascites (25 with malignant exudates, 13 with nonmalignant exudates, and 23 with transudates). Patients with sepsis were excluded. Correlation tests and one-way ANOVAs were used for comparisons between different groups. Discriminant analyses were used to assess the significance of each parameter in the differentiation process. Correct classification of 100% of cases required the use of all 57 ascitic fluid measurements in the model, which was not considered practical in clinical diagnosis. Discriminant analysis showed that five ascitic fluid measurements-total protein, LDH, TNF-alpha, C4, and haptoglobin-were sufficient for a model to correctly classify 89% of cases. Cross-validation showed that 70% of unknown cases were correctly classified using this model. In conclusion, we have shown that five easily taken protein measurements in the ascitic fluid can differentiate to a large extent between cases with ascites and have proposed a relatively simple statistical model with these parameters that could be developed to be extremely useful in the clinical setting.
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PMID:Discrimination between malignant and nonmalignant ascites using serum and ascitic fluid proteins in a multivariate analysis model. 1074 24

A 68-year-old man was admitted to our hospital because of fever, jaundice and hepatosplenomegaly. A diagnosis of diffuse large cell, B-cell type malignant lymphoma, associated with hemophagocytic syndrome (LAHS), was made. CT scan revealed lymphadenopathy in the abdominal cavity and multiple tumors in the spleen. Performance status and hepatic coma grade were 4 and II, respectively. Laboratory findings showed bicytopenia (Hb 9.9 g/dl, platelet 35 x 10(3)/microliter), severe liver dysfunction (ALP 1,115 U/l, gamma-GTP 437 U/l, T.Bil 15.4 mg/dl, D.Bil 12.8 mg/dl) and elevated levels of beta 2 microglobulin (12.9 mg/dl), ferritin (2,300 ng/ml) and sIL-2 receptor (36,900 U/ml). Plasma exchange (PE) and continuous hemodiafiltration (CHDF) enabled the patient to undergo diagnostic procedures, irradiation (total 34 Gy) and chemotherapy. Biopsy specimens revealed infiltration of lymphoma cells into the liver and bone marrow. We measured the blood concentrations of TNF-alpha, IL-6, and IL-8 before and after PE and CHDF by the ELISA method, and found normalization of hypercytokinemia after the procedure. It was suggested that initial treatment with PE and CHDF was effective for control of HPS, enabling us to perform chemotherapy for the lymphoma.
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PMID:[Plasma exchange and continuous hemodiafiltration as an initial treatment for diffuse large B-cell lymphoma-associated hemophagocytic syndrome]. 1186 63


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