Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biosynthesis of nitric oxide (NO) from L-arginine modulates activity of iron-dependent enzymes, including mitochondrial acontiase, an [Fe-S] protein. We examined the effect of NO on the activity of iron regulatory factor (IRF), a cytoplasmic protein which modulates both ferritin mRNA translation and transferrin receptor mRNA stability by binding to specific mRNA sequences called iron responsive elements (IREs). Murine macrophages were activated with interferon-gamma and lipopolysaccharide to induce NO synthase activity and cultured in the presence or absence of NG-substituted analogues of L-arginine which served as selective inhibitors of NO synthesis. Measurement of the nitrite concentration in the culture medium was taken as an index of NO production. Mitochondria-free cytosols were then prepared and aconitase activity as well as IRE binding activity and induction of IRE binding activity were correlated and depended on NO synthesis after IFN-gamma and/or LPS stimulation. Authentic NO gas as well as the NO-generating compound 3-morpholinosydnonimine (SIN-1) also conversely modulated aconitase and IRE binding activities of purified recombinant IRF. These results provide evidence that endogenously produced NO may modulate the post-transcriptional regulation of genes involved in iron homeostasis and support the hypothesis that the [Fe-S] cluster of IRF mediates iron-dependent regulation.
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PMID:Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. 750 26

Iron-regulatory protein (IRP) is a master regulator of cellular iron homeostasis. Expression of several genes involved in iron uptake, storage, and utilization is regulated by binding of IRP to iron-responsive elements (IREs), structural motifs within the untranslated regions of their mRNAs. IRP-binding to IREs is controlled by cellular iron availability. Recent work revealed that nitric oxide (NO) can mimic the effect of iron chelation on IRP and on ferritin mRNA translation, whereas the stabilization of transferrin receptor mRNA following NO-mediated IRP activation could not be observed in gamma-interferon/lipopolysaccharide-stimulated murine macrophages. In this study, we establish the function of NO as a signaling molecule to IRP and as a regulator of mRNA translation and stabilization. Fibroblasts with undetectable levels of endogenous NO synthase activity were stably transfected with a cDNA encoding murine macrophage inducible NO synthase. Synthesis of NO activates IRE binding, which in turn represses ferritin mRNA translation and stabilizes transferrin receptor mRNA against targeted degradation. Furthermore, iron starvation and NO release are shown to be independent signals to IRP. The posttranscriptional control of iron metabolism is thus intimately connected with the NO pathways.
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PMID:Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts. 753 89

Thioglycolate-elicited murine macrophages from genetically susceptible A/J mice activated with lipopolysaccharide (LPS) and infected with Legionella pneumophila in vitro evince marked inhibition of intracellular growth of this bacterium. The mechanism of inhibition by LPS-activated macrophages in terms of replication of this intracellular pathogen is unclear. LPS activation of murine macrophages induced a downshift in transferrin receptor (TfR) expression and reduction in cellular iron content, and this was correlated with augmented intracellular growth of Legionella in the cells. When LPS-stimulated macrophages were first saturated with iron, partial reversion of L. pneumophila growth restriction was observed. However, an excess of exogenous L-tryptophan (Trp) did not reverse this growth inhibition, nor did supplementation of the macrophage culture medium with both iron and Trp. The antilegionella activity of the macrophages induced by LPS activation was independent of reactive oxygen intermediates (ROI), since the scavengers catalase, superoxide dismutase, mannitol, and thiourea had no effect on growth restriction. Likewise, notwithstanding the ability of LPS-activated macrophages to synthesize reactive nitrogen intermediates (RNI), which was inhibited by L-arginine analogs NG-monomethyl-L-arginine and L-aminoguanidine), as well as by incubation in arginine-free medium, their ability to inhibit the intracellular replication of L. pneumophila was not affected. Thus, we conclude that LPS-activated macrophages inhibit the intracellular growth of L. pneumophila partially by iron-dependent, Trp-independent, and ROI- and RNI-independent mechanisms. We also suggest that additional unknown mechanisms are involved, since complete reversion was not obtained.
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PMID:LPS inhibits the intracellular growth of Legionella pneumophila in thioglycolate elicited murine peritoneal macrophages by iron-dependent, tryptophan-independent, oxygen-independent, and arginine-independent mechanisms. 782 75

To elucidate the role of the oxidative burst in macrophage resistance to Legionella infection, we examined a murine macrophage-like cell line, J774.1, for permissiveness to Legionella growth, using a mutant that has a selective defect in the oxidative burst after lipopolysaccharide (LPS) stimulation. Legionella pneumophila serogroup 1 was infected into J774.1 monolayers, and then the extent of bacterial growth was estimated by a CFU assay. Both the parental cell line, JA-4, and the LPS-resistant mutant, LPS1916, were permissive for Legionella growth but became nonpermissive after pretreatment with gamma interferon. However, pretreatment of LPS1916 cells with LPS failed to inhibit bacterial growth, although LPS-treated JA-4 cells exhibited inhibited multiplication of the bacteria. The bacterial growth inhibition in JA-4 and mutant LPS1916 cells was correlated with the extent of the oxidative burst in the cells, as judged by cytochrome c reduction but not nitrite production. Neither transferrin receptor expression nor the iron content in JA-4 and LPS1916 cells, with or without LPS treatment, was correlated with suppression of Legionella growth. These results suggest that the restriction of Legionella growth in J774.1 cells is due to a bactericidal effect of the oxidative burst rather than reduction of the iron supply to the intracellular bacteria and that the effectors are reactive oxygen intermediates and not reactive nitrogen intermediates.
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PMID:Difference in Legionella pneumophila growth permissiveness between J774.1 murine macrophage-like JA-4 cells and lipopolysaccharide (LPS)-resistant mutant cells, LPS1916, after stimulation with LPS. 796 Jan 21

In chronic inflammation it is reported that serum iron is depleted and hepatic iron is increased because of reticuloendothelial system iron blockade. However, recent studies indicate that hepatic parenchymal cells increase the uptake of transferrin-bound iron after in vivo stimulation with bacterial lipopolysaccharide, suggesting that endotoxemia itself or lipopolysaccharide-induced production of inflammation-related cytokines may also be responsible for this phenomenon. In this study the actions of inflammation-related cytokines on the synthesis of iron-binding proteins (transferrin and ferritin) and transferrin receptor and the uptake of transferrin-bound iron were investigated in a human hepatoblastoma cell line, HepG2, which is the most commonly used cell line for examining the regulation of hepatic protein synthesis by cytokines. The cells were exposed to interleukin-1 beta, interleukin-6 or tumor necrosis factor-alpha separately for 24 hr. In each cytokine treatment group, the level of transferrin, which is secreted into the conditioned medium, was found to be decreased compared with that of untreated cells. On the other hand, the biosynthesis of ferritin was markedly elevated after the same treatment. This increase in ferritin by cytokine treatment was diminished when deferoxamine was used concomitantly to deplete intracellular chelatable iron. After stimulation with interleukin-1 beta, interleukin-6 or tumor necrosis factor-alpha, 59Fe-labeled transferrin uptake into the cells was increased by 36%, 48%, or 18%, respectively, and this uptake was inhibited by the addition of excess unlabeled transferrin. A binding study with 125I-labeled diferric transferrin revealed that the three cytokines increased the number of transferrin receptors on the cell surface by 1.15-fold to 1.35-fold.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of iron metabolism in HepG2 cells: a possible role for cytokines in the hepatic deposition of iron. 840 63

The expression of transferrin receptors marked by the monoclonal antibody OX-26 and localisation of iron was studied in epiplexus cells in the lateral ventricles of different aged rats subjected to the challenge of the bacterial toxin, lipopolysaccharide, and treatment with interferon-gamma. Transferrin receptor expression in epiplexus cells was extremely low in normal rats, but was vigorously elevated in rats receiving intraperitoneal injections of lipopolysaccharide (LPS); other antigens such as complement type 3 receptors immunostained with OX-42 and macrophage antigen marked by ED-1 were also notably augmented. After 6 successive intraperitoneal injections of interferon-gamma, the expression of transferrin receptors showed only a moderate increase. Using Perls' staining method, some iron-containing epiplexus cells were observed in early normal postnatal rats, but their number was markedly decreased with age. After LPS administration, a moderate increase in the number of iron-containing epiplexus cells was observed in different aged rats. The significance of the upregulation and vigorous expression of transferrin receptors on epiplexus cells is speculative. One possible explanation would be that they facilitate an increase in the acquisition of iron by these cells for storage, oxidative killing and/or immunological activation. The localisation of iron in the choroid plexus in the lateral ventricles suggests that the latter may function as an important storage organ for iron. Present results also suggest the presence of an efficient transport system for the transfer of iron across the interface of the blood and cerebrospinal fluid.
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PMID:Expression and upregulation of transferrin receptors and iron uptake in the epiplexus cells of different aged rats injected with lipopolysaccharide and interferon-gamma. 858 59

Iron-regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that bind to stem-loop structures known as iron-responsive elements (IREs). IREs are located in the 5'- or 3'-untranslated regions (UTRs) of specific mRNAs that encode proteins involved in iron homeostasis. The binding of IRPs to 5' IREs represses translation of the mRNA, whereas the binding of IRPs to 3' IREs stabilizes the mRNA. IRP1 and IRP2 binding activities are regulated by intracellular iron levels. In addition, nitric oxide (NO.) increases the affinity of IRP1 for IREs. The role of NO. in the regulation of IRP1 and IRP2 in rat hepatoma cells was investigated by using the NO.-generating compound S-nitroso-N-acetylpenicillamine (SNAP), or by stimulating cells with multiple cytokines and lipopolysaccharide (LPS) to induce NO. production. Mitochondrial and IRP1 aconitase activities were decreased in cells producing NO(.). NO. increased IRE binding activity of IRP1, but had no effect on IRE binding activity of IRP2. The increase in IRE binding activity of IRP1 was coincident with the translational repression of ferritin synthesis. Transferrin receptor (TfR) mRNA levels were increased in cells treated with NO.-generating compounds, but not in cytokine- and LPS-treated cells. Our data indicate that IRP1 and IRP2 are differentially regulated by NO. in rat hepatoma cells, suggesting a role for IRP1 in the regulation of iron homeostasis in vivo during hepatic inflammation.
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PMID:Differential regulation of IRP1 and IRP2 by nitric oxide in rat hepatoma cells. 863 20

Previous studies from our laboratory have demonstrated that freshly isolated peripheral blood monocytes from localized juvenile periodontitis (LJP) patients secrete more prostaglandin E2 (PGE2) after stimulation by lipopolysaccharide (LPS) than do monocytes from healthy subjects. However, it is not clear if the altered function of LJP monocytes is intrinsic to the cells or is induced by the persistent infection of the periodontium. The present study was designed to compare PGE2 secretion by freshly-isolated peripheral blood monocytes (FIM) from LJP and control subjects to in vitro monocyte-derived macrophages (MDM) from the same subjects. We also examined monocyte maturation into macrophage-like cells and the cell-surface expression of the LPS, receptor, CD14 during the culture period. FIM from LJP patients and controls were stimulated by different concentrations of LPS (O to 30 micrograms/ml) for 24 hours. These experiments were performed immediately after cell separation and after 10 days in culture, which allowed differentiation of monocytes into MDM. PGE2 levels in the culture media were determined using a radioimmunoassay. Cell surface expression of CD71, a cell maturation marker, and CD14 were assayed by cell-ELISA in relation to beta-2-microglobulin. LPS-stimulated FIM from LJP patients secreted 3 to 4 times more PGE2 than control FIM at all LPS concentrations tested. After 10 days in culture, the LJP MDM secretion of PGE2 reduced to control MDM level of PGE2 secretion. These levels of PGE2 secretion were comparable to PGE2 secretion from FIM of controls. Cell maturation, as verified by CD71 expression, was found not to differ between the groups. However, the expression of CD14 by LJP FIM was much lower than on control FIM (approximately equal to 50%). After 5 or 10 days in culture, MDM from both control and LJP subjects expressed comparable amounts of CD14. The results suggest that in vitro conditions reverse the hypersensitivity of LJP monocytes to LPS into control levels and CD14 expression is not correlated to the hyper-responsiveness of the cells to LPS.
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PMID:Prostaglandin E2 secretion, cell maturation, and CD14 expression by monocyte-derived macrophages from localized juvenile periodontitis patients. 870 53

The release of cytokines and prostaglandins (PG) by peritoneal macrophages (PM luminal diameter of) may influence the cytokine network controlling peritoneal inflammation and in the long-term the function of the peritoneum as a dialysis membrane. In the present study, an evaluation of the long-term effects of peritoneal dialysis on the release of cytokines and prostaglandins, and the expression of surface markers of cellular maturation on blood and mononuclear cells has been performed in patients during their first year on CAPD. Spontaneous release of tumour necrosis factor alpha (TNF alpha) and interleukins 6 (IL-6) by PM luminal diameter of, after 4 or 24 hours in culture, increased significantly with time on CAPD, while there was a small but significant decrease in release of prostaglandin E2 (PGE2). Production of TNF alpha and IL-6 was enhanced following incubation of the cells with lipopolysaccharide (LPS), but the effect of LPS was proportionally greater on blood monocytes than on PM luminal diameter of. There was a significant increase in the concentrations of PGE2 and 6-keto-prostaglandin F1 alpha in overnight dwell peritoneal dialysis effluent with time on CAPD. The levels of TNF alpha and IL-6 in uninfected PDE were below the detection limit of the immunoassay over the whole time period studied. Expression of CD15, which correlates with immaturity, by PM luminal diameter of and blood monocytes increased with time on CAPD, while expression of CD11c, a marker of maturation, decreased on blood monocytes, but did not change significantly on PM luminal diameter of. There was also a slight increase in expression of transferrin receptor in both PM luminal diameter of and monocytes, but this did not reach statistical significance. These findings suggest that peritoneal macrophages and blood monocytes isolated from CAPD patients over a one year period become increasingly immature with time, and this is accompanied by a significant modulation of their ability to secrete inflammatory cytokines. Dysregulation of macrophage function may have important consequences with respect to inflammatory processes and the long-term function of the peritoneal membrane in CAPD patients.
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PMID:Longitudinal evaluation of peritoneal macrophage function and activation during CAPD: maturity, cytokine synthesis and arachidonic acid metabolism. 882 40

The rat monoclonal antibody LR-1 was initially described to be reactive with an antigen present on murine splenic B lymphocytes. However, flow-cytometric analyses of cells obtained from thymus, bone marrow, spleen, and lymph nodes showed that LR-1 stained approximately 95, 95, 60-70 and 20% of cells present within these tissues in normal DBA/2 mice. The marker recognized by LR-1 was present on peripheral erythrocytes and splenic dendritic cells, and activation with lipopolysaccharide A further increased expression of this antigen by splenic B cells. This particular tissue and cellular distribution was similar to that delineated with monoclonal antibodies reactive with heat-stable antigen (HSA). Duallabelling studies were conducted to compare the reactivity patterns of LR-1 and the HSA-reactive monoclonal antibody J11d and indicated that both antibodies recognized splenocytes bearing B cell (IgM) or erythroid (TER-119, CD71) but not T cell (CD4, CD8) markers. Splenocytes exposed to phosphoinostol-specific phospholipase C showed marked reduction in LR-1 binding, indicating that this antibody recognized a glycosylphosphatidylinositol-anchored cell surface protein, consistent with the known structure of HSA. Mixing of LR-1 with the HSA-specific antibodies J11d or M1/69 provided flow-cytometric profiles indistinguishable from those obtained with either antibody alone. However, LR-1 inhibited M1/69 binding to splenocytes by 83%, while J11d reduced M1/69 binding to these cells by only 18%. This finding suggested that LR-1 and M1/69 recognize identical splenic HSA epitopes, while LR-1 and J11d bind distinct antigenic determinants of spleen HSA. Western blot analysis of splenocyte, thymocyte, bone marrow cell and erythrocyte detergent extracts revealed that LR-1 reacted with glycoforms of HSA of known molecular weights (30-55 kD). Thus, LR-1 recognizes HSA, the murine analogue of human CD24, and will be a useful reagent with which to investigate the role of HSA in the immune response and hematopoiesis.
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PMID:Monoclonal antibody LR-1 recognizes murine heat-stable antigen, a marker of antigen-presenting cells and developing hematopoietic cells. 891 16


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