Transferrin and iron salts modulate differently tumor necrosis factor-α secretion by cultured human mononuclear cells1–3 (original) (raw)
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Relationship between TNF-α and iron metabolism in differentiating human monocytic THP-1 cells
2000
The human monocytic cell line THP-1 differentiates along the macrophage line after phorbol-12myristate-13-acetate (PMA) supplementation and can be stimulated to secrete tumour necrosis factor a (TNF-a) by interferon g (IFN-g) 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 PMAdifferentiating cells induced the expression of TNF-a mRNA and TNF-a secretion to levels even higher than those induced by IFN-g alone. The iron chelator desferrioxamine showed the opposite effect and reduced TNF-a release. In
Relationship between TNF-alpha and iron metabolism in differentiating human monocytic THP1 cells
British Journal of Haematology, 2000
The human monocytic cell line THP-1 differentiates along the macrophage line after phorbol-12myristate-13-acetate (PMA) supplementation and can be stimulated to secrete tumour necrosis factor a (TNF-a) by interferon g (IFN-g) 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 PMAdifferentiating cells induced the expression of TNF-a mRNA and TNF-a secretion to levels even higher than those induced by IFN-g alone. The iron chelator desferrioxamine showed the opposite effect and reduced TNF-a release. In
Iron absorption and distribution in TNFΔARE/+ mice, a model of chronic inflammation
Journal of Trace Elements in Medicine and Biology, 2010
Hemizygous TNF DARE/ + mice are a murine model for chronic inflammation. We utilized these animals to study iron-kinetics and corresponding protein expression in an iron-deficient and iron-adequate setting. 59 Fe-absorption was determined in ligated duodenal loops in vivo. Whole body distribution of i.v. injected 59 Fe was analysed, and the organ specific expression of ferroportin, transferrin receptor-1, hepcidin and duodenal DMT-1 was quantified by real-time PCR and Western blotting.
Journal of Experimental Medicine, 1977
In a previous paper (1) we have reported results which indicated that lactoferrin (Li~, 1 the iron-binding protein from the specific granules of neutrophilic leukocytes might be involved in the hyposideremia occurring during inflammation. The role of Lf in this phenomenon is related to the high affinity of Lf for iron (2) and the existence of a receptor for this protein on the membrane of macrophages (3). In the present work, we have further investigated the Lf-macrophage interaction in relation to the ingestion of the protein, its intracellular fate, and finally, the transfer of iron from Lf into ferritin. Materials and Methods Cells. Mouse peritoneal macrophages (MPM) were harvested from NMRI female mice by rinsing the peritoneal cavity with 5 ml of basal medium of Eagle (BME), containing 10 U/ml of heparin and 50 ~g/ml of streptomycin. After centrifugation at 100 g for 10 rain, the cells were resuspended in BME supplemented with 10% heat inactivated fetal calf serum (FCS) and with penicillin 50 U/ml and streptomycin (50 ~g/ml), and distributed in Linbro tissue culture plates (Linbre Chemical Co., New Haven, Conn.) (10 s cells per well); after incubation at 37°C, in a 5% COs atmosphere, the adherent macrophages were washed free from contaminating lymphocytes, and further incubated in the same conditions with the appropriate concentration of radiolabeled protein. The mean yield of adherent macrophages was 3 × l0 s cells per well. Reagents, Human Lf was purified in an iron (Fe)-free form from milk by chromatography on carboxylmethyl-Sephadex (4) (Pharmacia Fine Chemicals Inc., Piscataway, N. J.). Human transferrin (Ti~ was purchased from Behring-Werke AG, Marburg/Lahn, West Germany. Horse spleen ferritin and Triton X-100 were from Sigma Chemical Co., St. Louis, Mo. Lf and Tf were labeled with ~QFe by mixing the protein with °SFe citrate in the presence of bicarbonate. The degree of iron saturation was calculated from the specific radioactivity of the metal. Labeling of ApoLf and FeLf with 125I was performed by means of the chloramine T procedure. The labeled proteins were separated from excess isotope by filtration on Sephadex G 25.
Parenteral iron compounds sensitize mice to injury-initiated TNF-α mRNA production and TNF-α release
American Journal of Physiology-Renal Physiology, 2004
Intravenous Fe is widely used to treat anemia in renal disease patients. However, concerns of potential Fe toxicity exist. To more fully define its spectrum, this study tested Fe's impact on systemic inflammation following either endotoxemia or the induction of direct tissue damage (glycerol-mediated rhabdomyolysis). The inflammatory response was gauged by tissue TNF-α message expression and plasma TNF-α levels. CD-1 mice received either intravenous Fe sucrose, -gluconate, or -dextran (FeS, FeG, or FeD, respectively; 2 mg), followed by either endotoxin (LPS) or glycerol injection 0–48 h later. Plasma TNF-α was assessed by ELISA 2–3 h after the LPS or glycerol challenge. TNF-α mRNA expression (RT-PCR) was measured in the kidney, heart, liver, lung, and spleen with Fe ± LPS treatment. Finally, the relative impacts of intramuscular vs. intravenous Fe and of glutathione (GSH) on Fe/LPS- induced TNF-α generation were assessed. Each Fe preparation significantly enhanced LPS- or muscle...
Clonal analysis of the effect of iron on human cytotoxic and proliferating T lymphocytes
Immunology and Cell Biology, 1990
The immunoregulatory effect ofnon-transferrin-bound iron (Fe'"'') on the proliferative and cytotoxic responses of normal human T lymphocytes was studied using a sensitive limit-dilution teehnique capable of detecting the responses of individual lymphocytes. Iron, present in the form of ferric citrate at concentrations from 003 to I'0 mmol/L. significantly reduced the cloning frequency of peripheral blood T lymphocytes. The eliect ol'iron appeared, however, to be targeted to individual clones in that some clones thai did grow in the presence of iron achieved a normal rateof prolileralion. Thus, iron was not non-spccifically toxic. At these same concentrations ferric cilrate also produced significant reductions in Ihe cloning frequency of CD4 f CD8-precursor T lymphocytes. Reductions in the response of T lymphocyte precursors capable of cytotoxic activity occurred in the presence of ferric cilrate from ()•! lo I •() mmol/L. These data support the hypothesis that non-translerrin-bound iron has an immunoregulatory role in ccli-mcdiated immunity.
Hemizygous TNF DARE/ + mice are a murine model for chronic inflammation. We utilized these animals to study iron-kinetics and corresponding protein expression in an iron-deficient and iron-adequate setting. 59 Fe-absorption was determined in ligated duodenal loops in vivo. Whole body distribution of i.v. injected 59 Fe was analysed, and the organ specific expression of ferroportin, transferrin receptor-1, hepcidin and duodenal DMT-1 was quantified by real-time PCR and Western blotting. Duodenal 59 Fe-lumen-to-body transport was not affected by the genotype. Duodenal 59 Fe-retention was increased in TNF DARE/ + mice, suggesting higher 59 Fe-losses with defoliated enterocytes. Iron-deficiency increased duodenal 59 Fe-lumen-to-body transport, and higher duodenal 59 Fe-tissue retention went along with higher duodenal DMT-1, ferroportin, and liver hepcidin expression. TNF DARE/ + mice significantly increase their 59 Fe-content in inflamed joints and ilea, and correspondingly reduce splenic 59 Fe-content. Leukocyte infiltrations in the joints suggest a substantial shift of iron-loaded RES cells to inflamed tissues as the underlying mechanism. This finding was paralleled by increased non-haem iron content in joints and reduced haemoglobin and haematocrit concentrations in TNF DARE/ + mice. In conclusion, erythropoiesis in inflamed TNF DARE/ + mice could be iron-limited due to losses with exfoliated iron-loaded enterocytes and/or to increased iron-retention in RES cells that shift from the spleen to inflamed tissues.
Iron, infection and immune function
Proceedings of the Nutrition Society, 1993
A decrease in circulating Fe, or hypoferraemia, is one of the most constant features of infectious disease. Since Fe deprivation in bacterial cultures is regularly associated with inhibition of growth, it has been suggested that Fe deficiency may represent an important defence mechanism (Weinberg, 1990). The term 'nutritional immunity' has been introduced by Kochan (1973) to underline the importance of Fe deprivation as a key mechanism limiting the growth of invading organisms. Interleukin-1 (IL-l), a protein released by mononuclear phagocytes in response to microbial invasion, is a key mediator in the inflammatory reaction and is directly responsible for the hypoferraemia of inflammation (Dinarello, 1984). It enhances the synthesis of a number of acute-phase proteins such as fibrinogen, haptoglobin, ceruloplasmin, amyloid A protein and ferritin (Fig. 1). The result of increased ferritin synthesis is a block in Fe release resulting in reduced serum Fe levels. Because of the paucity of clinical information supporting the significance of Fe deficiency or overload in determining the severity of infectious disease in man, the nutritional immunity hypothesis has remained a topic of continued controversy (Hershko & Peto, 1988). This controversy is of more than academic interest, since both Fe deficiency and infectious diseases are common conditions, and Fe supplementation in some populations may resolve one problem while aggravating the other. In the text that follows, I shall discuss briefly the importance of microbial Fe requirements, the role of Fe