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

Statins were shown to possess immunomodulating properties, but the mechanisms of statin effects on the immune system are poorly understood. We analyzed the influence of statins on professional antigen-presenting dendritic cells (DC). Immature DC were cultivated from monocytes of healthy donors. DC maturation was induced by lipopolysaccharide (LPS; 1 microg/mL). Unstimulated and LPS-stimulated DC were treated with simvastatin or atorvastatin (0.1-1 microM). The expression of CD40, CD83, CD86, and human leukocyte antigen-DR on unstimulated and LPS-stimulated DC was reduced significantly by statins, and the expression of Toll-like receptor 2 (TLR2) and TLR4 on LPS-stimulated DC was enhanced temporarily. Statins caused a significant reduction of endocytosis of fluorescein isothiocyanate-dextran by DC. Statins significantly inhibited the basal secretion of interleukin (IL)-6, IL-8, IL-12, and tumor necrosis factor alpha from unstimulated DC, and their release from LPS-stimulated DC was enhanced. In mixed leukocyte reaction, preincubation of LPS-stimulated DC with statins significantly suppressed their clustering with T cells and their ability to induce T cell proliferation, CD71, and CD25 up-regulation on T cells and the secretion of interferon-gamma and IL-2 from T cells. In conclusion, this study showed that statins suppressed endocytosis, basal secretion of proinflammatory cytokines, and the ability of DC to induce T cell proliferation, activation, and T helper cell type 1 differentiation. However, statin preincubation of LPS-stimulated DC caused a further increase in their secretion of proinflammatory cytokines.
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PMID:Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. 1638 46

The effects of high-linear energy transfer (LET) radiation on immune function have not been clearly established. The major goal of this study was to evaluate leukocyte responses after whole-body exposure to high-LET radiation. C57BL/6 mice were exposed to 0, 0.5, 2 and 3 Gy (56)Fe(26+) particles (1055 MeV/nucleon, 148.2 keV/microm) and killed humanely 4 days after exposure. Spontaneous synthesis of DNA in blood and spleen cells was increased significantly in groups receiving either 2 or 3 Gy (P < 0.001). In contrast, a significant depression in the response of T lymphocytes to phytohemagglutinin (PHA) and concanavalin A (ConA) was noted (P < 0.005); the response to lipopolysaccharide (LPS), a B-cell mitogen, was similar among groups. A cytometric bead array assay revealed that the level of tumor necrosis factor alpha (Tnfa) secreted by splenocytes increased significantly with increasing (56)Fe-particle dose (P < 0.05); interferon gamma, interleukin2 (Il2), Il4 and Il5 were unaffected. Flow cytometry analysis showed that 2 and 3 Gy markedly reduced splenic mononuclear cells expressing the activation markers CD25 and CD71, both with and without the T-cell marker CD3 (P < 0.05); proportions also varied significantly. Similar patterns were noted in mononuclear and granular cells with adhesion markers CD11b and, to a lesser extent, CD54 (P < 0.05). The results show that a single, acute exposure to high-LET radiation induced changes that can profoundly alter leukocyte functions. The implications of the data are discussed in relation to low-LET radiation, altered gravity, and space flight.
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PMID:Acute effects of iron-particle radiation on immunity. Part II: Leukocyte activation, cytokines and adhesion. 1639 65

Rafts resemble cholesterol- and glycosphingolipid-enriched, liquid-ordered plasma membrane microdomains, showing resistance to nonionic detergents, and are involved in various cellular processes. In the present study, we have tested surface antigens on resting and lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes for their detergent resistance (i.e. raft-association), by flow cytometry. Constitutive (CD14, CD32, CD55), or LPS-induced (CD81) raft-association, and detergent solubility (i.e. exclusion of rafts) (CD71) of monocyte antigens in the presence of 0.01% Triton X-100 are clearly demonstrated. Flow cytometric detergent insolubility is a powerful tool for rapid screening the raft-association of monocyte antigens in a whole-blood assay.
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PMID:A flow cytometric screening test for detergent-resistant surface antigens in monocytes. 1647 17

The activation of cellular inflammatory response is tightly linked to induced production of reactive oxygen species (ROS) and nitric oxide (NO), which in turn have been identified as important regulators of cellular iron metabolism. In the present study, we have used the microglia cell line BV-2 and the neuroblastoma cell line N2a to study the regulatory effects of the microbial agent lipopolysaccharide (LPS) on the expression of the transferrin receptor (TfR) and ferritin in cell lines with different characteristics. The receptor mainly responsible for LPS recognition is the Toll-like receptor 4 (TLR4) that triggers a variety of intracellular signalling cascades leading to the induction of transcription of target genes involved in the innate immune response. Among the pathways to be activated is the MAPK cascade leading to the activation of nuclear factor-kappaB that induces transcription of a variety of genes, e.g., inducible nitric oxide synthase (iNOS). The TLR4-mediated LPS response also induces the production of ROS through a mechanism(s) suggested to involve the activation of NADPH oxidase(s). This study shows that exposure of BV-2 and N2a cells to LPS results in decreased TfR protein levels and increased H-ferritin mRNA levels. The LPS down-regulatory effect on TfR protein expression is abolished by the NADPH oxidase inhibitor diphenyliodonium (DPI) but is not affected by the free radical scavenger N-acetyl-L-cysteine (NAC) or the iNOS inhibitor aminoguanidine (AG). The increased H-ferritin mRNA levels in response to LPS are not affected by DPI, NAC, or AG.
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PMID:NADPH oxidase inhibitor diphenyliodonium abolishes lipopolysaccharide-induced down-regulation of transferrin receptor expression in N2a and BV-2 cells. 1688 Oct 50

Inflammation generates various changes in body iron homeostasis, including iron sequestration in the reticuloendothelial system with ensuing hypoferremia and anemia of chronic disease. Increased iron accumulation is caused by hepcidin-mediated down-regulation of the iron export protein ferroportin and higher iron uptake. However, enhanced iron acquisition by macrophages cannot be accounted for by the previously reported transferrin receptor (TfR1) down-regulation in macrophages exposed to lipopolysaccharide (LPS)/interferon gamma (IFNgamma) because it impairs a major iron uptake mechanism. Because TfR1 is up-regulated by the hypoxia-inducible factor (HIF-1), we investigated the effect of inflammatory and anti-inflammatory signals on HIF-1-mediated TfR1 gene expression. Exposure of mouse macrophages (RAW 264.7 and J774A.1 cells or peritoneal macrophages) to LPS/IFNgamma up-regulated NF-kappaB, which in turn rapidly and transiently activated HIF-1-dependent TfR1 expression and iron uptake. Activation of an anti-inflammatory pathway by pre-exposure to the adenosine A(2A) receptor agonist CGS21680 prevented the inducing effect of LPS/IFNgamma on HIF-1 and TfR1 expression by inhibiting NF-kappaB activity, whereas treatment with CGS21680 alone increased HIF-1-mediated TfR1 expression by means of an NF-kappaB-independent signaling pathway. In conclusion, an interplay of the HIF-1 and NF-kappaB pathways controls TfR1 transcription in inflammation. The consequent changes in TfR1 expression may be involved in modulating iron retention in inflammatory macrophages, thus possibly contributing to the development of hypoferremia in the early phases preceding the down-regulation of macrophage ferroportin by hepcidin.
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PMID:Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. 1851 69

Trypanosoma brucei, the causative agent of African sleeping sickness, evades the immune response by expressing a coat of variant surface glycoprotein (VSG). VSG is expressed from a single telomeric expression site (ES), along with a number of expression site associated genes (ESAGs). Thus far, the function of most ESAGs is unknown. One ES contains the serum resistance associated gene (SRA), which confers resistance to trypanosome lytic factor in T. b. rhodesiense. Only three other ESAGs -5, 6 and 7 - are present in this ES. ESAGs 6 and 7 encode a heterodimeric transferrin receptor, but the function of ESAG5 has not been identified. We present here a bioinformatic analysis of ESAG5 and distinguish between T. brucei-specific ESAGs and Genes Related to ESAG5 (GRESAGs), which occur outside of ESs in chromosomal-internal contexts. Further, a genome-wide survey of these genes across kinetoplastids identifies a family of GRESAG5s in a number of species. Analysis of phylogenetic relationships indicates that this family may have evolved from a single ancestral copy. Predicted properties of (GR)ESAG5 proteins indicate a glycosylated protein containing either a signal peptide or transmembrane domain. Further analysis indicates a possible relationship to the lipid transfer/lipopolysaccharide-binding family which includes the bactericidal/permeability increasing (BPI) protein. Together, these results provide insights into the structure and evolution of an important extended gene family, and present a number of testable hypotheses which will aid in elucidating the function of ESAG5.
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PMID:Bioinformatic insights to the ESAG5 and GRESAG5 gene families in kinetoplastid parasites. 1877 26

The study investigated the effects of red clover extract (RCE) on mouse T macrophages and lymphocytes in vitro. The cell toxic effect of RCE was estimated by MTT assay. Multiple-fluorescence staining plus flow cytometry were used to detect the effect of RCE on CD69/CD25/CD71 expression of mouse T lymphocytes stimulated by Con A; CFDA-SE staining plus flow cytometry were used to analyze the effect of RCE on proliferation of T lymphocytes activated by Con A; The effect of RCE on nitric oxide (NO) secretion of mouse macrophages stimulated by lipopolysaccharide (LPS) for 24 h was assayed by Griess reagent system. We found that RCE had potent anti-inflammatory effects on mice. RCE had little cell toxic effect on mouse lymphocytes and macrophages. RCE strongly inhibited the excessive production of inflammatory mediators (NO, CD69, CD25, CD71), in a dose-dependent manner, like cyclosporine A injection. RCE could inhibit proliferation of CD3+ T lymphocytes. These data suggested that RCE might exhibit anti-inflammatory effect by inhibiting the activation and proliferation of mouse lymphocytes and the NO secretion of mouse macrophages.
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PMID:Effects of red clover extract on the activation and proliferation of mouse T lymphocytes and the NO secretion of mouse macrophages. 1912 65

GA (gambogic acid) is a polyprenylated xanthone abundant in the resin of Garcinia morella and Garcinia hanburyi with a long history of use as a complementary and alternative medicine. The antitumour activity of GA has been well demonstrated and is thought to arise partly from the associated anti-inflammatory activity. Recent studies have indicated that the antitumour activity of GA is mediated by its ligation of TfR1 (transferrin receptor-1). Since the cellular expression of TfR1 is down-regulated by LPS (lipopolysaccharide), we hypothesized that an alternative pathway exists in immune cells, such as macrophages, where GA could mitigate the expression of pro-inflammatory genes. Here we demonstrate that GA inhibits the LPS-dependent expression of NF-kappaB (nuclear factor kappaB) target pro-inflammatory genes in macrophages. Western immunoblot, NF-kappaB-luciferase reporter and gel-shift analyses revealed that GA strongly blocked the activation of NF-kappaB induced by LPS, whereas 9,10-dihydro-GA, which lacks the reactive alpha,beta-unsaturated carbonyl group, was ineffective. Moreover, GA was able to decrease nuclear p65 levels in RAW264.7 macrophages, where the expression of TfR1 was down-regulated by RNA interference. in vitro kinase assays coupled with interaction studies using biotinylated GA as well as proteomic analysis demonstrated that IKKbeta [IkappaB (inhibitory kappaB) kinase-beta], a key kinase of the NF-kappaB signalling axis, was covalently modified by GA at Cys-179, causing significant inhibition of its kinase activity. Taken together, these results demonstrate the potent anti-inflammatory activity of GA.
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PMID:Gambogic acid covalently modifies IkappaB kinase-beta subunit to mediate suppression of lipopolysaccharide-induced activation of NF-kappaB in macrophages. 1914 Aug 5

Vascular inflammation and monocyte recruitment are initiating events in atherosclerosis that have been suggested to be caused, in part, by iron-mediated oxidative stress and shifts in the intracellular redox environment of vascular cells. Therefore, the objective of this study was to investigate whether the intracellular iron chelator, desferrioxamine (DFO), reduces inflammation and atherosclerosis in experimental mice. Treatment of C57BL/6J mice with DFO (daily intraperitoneal injection of 100 mg/kg body weight for two weeks) strongly inhibited lipopolysaccharide-induced increases of soluble cellular adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in the serum and activation of the redox-sensitive transcription factors, nuclear factor-kappaB and activator protein-1, in the aorta. Furthermore, treatment of apolipoprotein E-deficient (apoE-/-) mice with DFO (100 mg/kg, intraperitoneal, daily for 10 weeks) attenuated aortic atherosclerotic lesion development by 26% (P < 0.05). DFO treatment of apoE-/- mice also lowered serum levels of MCP-1 and gene expression of proinflammatory and macrophage markers in the aorta and heart, in parallel with increased protein expression of the transferrin receptor in the heart and liver. In contrast, DFO treatment had no effect on serum cholesterol and triglyceride levels. These data show that DFO inhibits inflammation and atherosclerosis in experimental mice, providing the proof-of-concept for an important role of iron in atherogenesis. Whether eliminating excess iron is a useful adjunct for the prevention or treatment of atherosclerosis in humans remains to be investigated.
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PMID:The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice. 2046 4

Anaemia is a common problem in septic patients. We tested whether lipopolysaccharide suppressed erythropoiesis and interfered with erythropoietin. Male mice (strain C57BL/6, n = 76) were injected Escherichia coli lipopolysaccharide (serotype O127:B8; 20 mg.kg(-1) intraperitoneally) or vehicle, followed by either erythropoietin (5000 IU.kg(-1) intraperitoneally) or vehicle, and killed after 24 or 72 h. Femur bone marrow cells were stained for Ter-119, CD71 and C-Kit antigen using specific flow cytometry gates for proerythroblasts, basophilic, polychromatic and orthochromatic erythroblasts, and peripheral blood reticulocytes were counted. Erythropoietin stimulated erythropoiesis, as evidenced by increased reticulocytes after 72 h by 197% and proerythroblasts by 50% (p < 0.05). Lipopolysaccharide alone decreased proerythroblasts by 53% and basophilic erythroblasts by 75% (p < 0.05). Orthochromatic erythroblasts doubled after lipopolysaccharide exposure (p < 0.05) without any increase in reticulocytes. Lipopolysaccharide completely suppressed erythropoietin's stimulatory effects and evoked a maturation block at the late stage of erythropoiesis. Lipopolysaccharide could cause anaemia in sepsis.
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PMID:Lipopolysaccharide interference in erythropoiesis in mice. 2235 62


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