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)

Cyclin-dependent kinase inhibitors such as p27(KIP1) have recently been shown to lead to cellular differentiation by causing cell cycle arrest, but it is unknown whether similar events occur in differentiating promyeloid cells. Hematopoietic progenitor cells undergo lineage-restricted differentiation, which is accompanied by expression of distinct maturation markers. Here we show that the classical growth factor insulin-like growth factor I (IGF-I) potently promotes vitamin D(3)-induced macrophage differentiation of promyeloid cells, as assessed by measurement of a coordinate increase in expression of the integrin alpha subunit CD11b, the CD14 lipopolysaccharide receptor, and the macrophage-specific esterase, alpha-naphthyl acetate esterase, as early as 24 h following initiation of terminal differentiation. Addition of IGF-I to cells undergoing vitamin D(3)-induced differentiation also leads to an early increase in expression of cyclin E, phosphorylation of the retinoblastoma tumor suppressor protein, and a doubling of the cell number. Early expression of CD11b (24 h) is simultaneously accompanied by inhibition in the expression of p27(KIP1). Cell cycle analysis with propidium iodide revealed that CD11b expression at 24 h following initiation of differentiation occurs at all phases of the cell cycle instead of only those cells arrested in G(0)/G(1). Similarly, development of a novel double-labeling intra- and extracellular flow-cytometric technique demonstrated that single cells expressing the mature leukocyte differentiation antigen CD11b can also incorporate the thymidine analog bromodeoxyuridine. Likewise, expression of the intracellular DNA polymerase delta cofactor/proliferating-cell nuclear antigen at 24 h is also simultaneously expressed with the surface marker CD11b, indicating that these cells continue to proliferate early in their differentiation program. Finally, at 24 h following induction of differentiation, IGF-I promoted a fourfold increase in the uptake of [(3)H]thymidine by purified populations of CD11b-expressing cells. Taken together, these data demonstrate that the initial steps associated with terminal macrophage differentiation occur concomitantly with progression through the cell cycle and that these very early differentiation events do not require the accumulation of p27(KIP1).
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PMID:Elevated cyclin E levels, inactive retinoblastoma protein, and suppression of the p27(KIP1) inhibitor characterize early development of promyeloid cells into macrophages. 1045 69

Bacteria of the genus Brucella are facultative intracellular pathogens which have developed the capacity to survive and multiply in professional and nonprofessional phagocytes. The genetic basis of this aspect of Brucella virulence is still poorly understood. To identify new virulence factors, we have adapted signature-tagged transposon mutagenesis, which has been used essentially in animal models, to an in vitro human macrophage infection model. A library of 1,152 Brucella suis 1330 tagged mini-Tn5 Km2 mutants, in 12 pools, was screened for intracellular survival and multiplication in vitamin D(3)-differentiated THP1 cells. Eighteen mutants were identified, and their attenuation was confirmed in THP1 macrophages and HeLa cells. For each avirulent mutant, a genomic fragment containing the transposon was cloned. The genomic DNA sequence flanking the transposon allowed us to assign functions to all of the inactivated genes. Transposon integration had occurred in 14 different genes, some of which were known virulence genes involved in intracellular survival or biosynthesis of smooth lipopolysaccharide (the virB operon and manB), thus validating the model. Other genes identified encoded factors involved in the regulation of gene expression and enzymes involved in biosynthetic or metabolic pathways. Possible roles in the virulence of Brucella for the different factors identified are discussed.
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PMID:Identification of Brucella suis genes affecting intracellular survival in an in vitro human macrophage infection model by signature-tagged transposon mutagenesis. 1067 41

Dendritic cells (DCs) play a central role in regulating immune activation and responses to self. DC maturation is central to the outcome of antigen presentation to T cells. Maturation of DCs is inhibited by physiological levels of 1alpha,25 dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and a related analog, 1alpha,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D(3) (D(3) analog). Conditioning of bone marrow cultures with 10(-10) M D(3) analog resulted in accumulation of immature DCs with reduced IL-12 secretion and without induction of transforming growth factor beta1. These DCs retained an immature phenotype after withdrawal of D(3) analog and exhibited blunted responses to maturing stimuli (CD40 ligation, macrophage products, or lipopolysaccharide). Resistance to maturation depended on the presence of the 1alpha,25(OH)(2)D(3) receptor (VDR). In an in vivo model of DC-mediated antigen-specific sensitization, D(3) analog-conditioned DCs failed to sensitize and, instead, promoted prolonged survival of subsequent skin grafts expressing the same antigen. To investigate the physiologic significance of 1alpha,25(OH)(2)D(3)/VDR-mediated modulation of DC maturity we analyzed DC populations from mice lacking VDR. Compared with wild-type animals, VDR-deficient mice had hypertrophy of subcutaneous lymph nodes and an increase in mature DCs in lymph nodes but not spleen. We conclude that 1alpha,25(OH)(2)D(3)/VDR mediates physiologically relevant inhibition of DC maturity that is resistant to maturational stimuli and modulates antigen-specific immune responses in vivo.
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PMID:Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. 1137 26

In addition to its calciotropic function, the secosteroid 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) has potent nonclassical effects. In particular, local production of 1,25D(3) catalyzed by the enzyme 1alpha-hydroxylase (1alpha-OHase) may act as an autocrine/paracrine immunomodulatory mechanism. To investigate the significance of this in vascular tissue the expression and function of 1alpha-OHase in human endothelial cells was characterized. Immunohistochemical and in situ hybridization analyses show, for the first time, the presence of 1alpha-OHase mRNA and protein in endothelial cells from human renal arteries as well as postcapillary venules from lymphoid tissue. Reverse transcription-PCR and Western blot analyses confirmed the presence of 1alpha-OHase in primary cultures of human umbilical vein endothelial cells (HUVEC). Enzyme activity in HUVEC (318 +/- 56 fmoles 1,25(OH)(2)D(3)/hr/mg protein) increased after treatment with tumor necrosis factor-alpha (1054 +/- 166, P < 0.01), lipopolysaccharide (1381 +/- 88, P < 0.01), or forskolin (554 +/- 56, P < 0.05). Functional studies showed that exogenously added 1,25(OH)(2)D(3) or its precursor, 25-hydroxyvitamin D(3) (25(OH)D(3)), significantly decreased HUVEC proliferation after 72 h of treatment (33% and 11%, respectively). In addition, after 24 h treatment, both 1,25(OH)(2)D(3) and 25(OH)D(3) increased the adhesion of monocytic U937 cells to HUVEC (159% and 153%, respectively). These data indicate that human endothelia are able to produce active vitamin D. The rapid induction of endothelial 1alpha-OHase activity by inflammatory cytokines suggests a novel autocrine/paracrine role for the enzyme, possibly as a modulator of endothelial cell adhesion.
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PMID:Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. 1185 65

The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is a potent immunomodulator known to affect T-cells through targeting antigen-presenting cells such as dendritic cells (DCs). We studied the effects of a novel nonhypercalcemic 1,25(OH)(2)D(3) analog, TX527, on DC differentiation, maturation, and function with respect to stimulation of a committed human GAD65-specific autoreactive T-cell clone. Continuous addition of TX527 impaired interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF)-driven DC differentiation as well as lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-induced maturation into Th1-promoting DC (DC1), as characterized by marked changes in DC morphology and abrogation of IL-12p70 release upon CD40 ligation. Addition of TX527 during maturation did not affect DC morphology but significantly changed DC cytokine profiles. The potential of treated DCs to alter the response pattern of committed autoreactive T-cells was found to depend on the timing of TX527 exposure. Continuously TX527-treated DCs significantly inhibited T-cell proliferation and blocked IFN-gamma, IL-10, but not IL-13 production, whereas DCs treated during maturation failed to inhibit T-cell proliferation but affected IL-10 and IFN-gamma production. Collectively, we provide evidence that nonhypercalcemic TX527 is a potent in vitro DC modulator, yielding DCs with the potential to change cytokine responses of committed autoreactive T-cells.
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PMID:Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). 1208 41

1Alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been shown to modulate the production of various cytokines or the expression of certain differentiation markers in human T cells or monocytes. Its effects on neutrophils, however, are poorly understood. In this paper, we show several lines of evidence indicating that neutrophils express functional vitamin D receptors (VDR). Sort-purified neutrophils from human peripheral blood expressed VDR mRNA at a level comparable to that of monocytes. As reported to occur in monocytes, protein expression of CD14 on the cell surface of neutrophils was augmented when the cells were incubated with 1,25(OH)2D3. To investigate the physiological roles for VDR in neutrophils, we investigated possible modulating effects of 1,25(OH)2D3 on the expression of several genes in lipopolysaccharide-stimulated neutrophils by using differential display analysis. Of the genes we identified, trappin-2/elafin/SKALP, which was originally reported to be an inhibitor of elastase, was induced in neutrophils by lipopolysaccharide, but was suppressed significantly in the presence of 1,25(OH)2D3. Under the same conditions, interleukin-1beta expression was also inhibited. These findings suggest that 1,25(OH)2D3 has a potential to affect the inflammatory process by modulating the expression of neutrophil genes.
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PMID:Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3. 1237 32

The liver is generally considered negative for the vitamin D nuclear receptor (VDR(n)), even though several studies have shown significant effects of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on liver cell physiology. The low abundance of VDR(n) in the liver led us to propose that hepatocytes (the largest hepatic cell population) were most likely negative for the receptor, whereas the small hepatic sinusoidal and ductular cell populations that contain cell types known to express VDR(n) in other tissues should express the receptor. Using freshly isolated cells from normal livers as well as biliary and epithelial hepatic cell lines, our data show that the human, rat, and mouse hepatocytes express very low VDR(n) messenger RNA (mRNA) and protein levels. In contrast, sinusoidal endothelial, Kupffer, and stellate cells of normal rat livers as well as the mouse biliary cell line BDC and rat hepatic neonatal epithelial SD6 cells clearly expressed both VDR(n) mRNA and protein. In addition, specimens of human hepatocarcinoma as well as intrahepatic colon adenocarcinoma metastases were also found to express the VDR(n) gene transcript. Kupffer, stellate, and endothelial cells responded to 1,25(OH)(2)D(3) by a significant increase in the CYP24, indicating that the VDR(n) is fully functional in these cells. In conclusion, selective hepatic cell populations are targets for the vitamin D endocrine/paracrine/intracrine system.
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PMID:The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. 1271 84

We searched for genes with expressions specific to human monocyte-derived dendritic cells (DCs) using differential display reverse transcription-polymerase chain reaction, and found that N-myc downstream regulated gene 2 (NDRG2), a member of a new family of differentiation-related genes, was expressed in DCs. While DCs derived from CD34(+) progenitor cells also showed strong NDRG2 expression, the corresponding mRNA expression was absent in other cell lines including monocytes, B cells, and NK cells. The inhibition of DC differentiation by dexamethasone or vitamin D(3) treatment down-regulated the expression of the NDRG2 gene in DCs. In addition, gene expression was induced in a myelomonocytic leukemia cell line, which is capable of differentiating into DCs in cytokine-conditioned culture. The level of NDRG2 gene expression in DCs was significantly higher than that of other members of the NDRG gene family. Finally, in contrast to the stable NDRG2 expression in CD40-stimulated DCs, the induction of DC maturation by lipopolysaccharide (LPS) resulted in the down-regulation of NDRG2 gene expression. This down-regulation is likely to be due to a modification and subsequent destabilization of NDRG2 mRNA, because co-treating with actinomycin D and LPS significantly blocked this LPS effect. Taken together, our results indicate that NDRG2 is expressed during the differentiation of DCs, and that NDRG2 gene expression is differentially regulated by maturation-inducing stimuli.
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PMID:Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells. 1457 61

Four multiparous lactating cows (175 to 220 d in milk) were used in a 4 x 4 Latin square design to assess the effects of four doses (0.0, 0.5, 1.0, 1.5 microg/kg of body weight) of lipopolysaccharide (LPS; Escherichia coli 0111:B4) on circulating concentrations of macrominerals and vitamin D metabolites. Treatments were dissolved in 100 ml of sterile saline and infused intravenously over a period of 100 min. Blood was sampled immediately before infusion (0 h), at 60-min intervals for 8 h, and at 24 and 48 h postinfusion. Vitamin D metabolites were analyzed in samples collected at 0, 2, 6, 24, and 48 h only. Serum Ca and P concentrations decreased after LPS infusion, but there was no effect on serum magnesium concentration. Plasma 25-OH vitamin D3 and 1,25-(OH)2 vitamin D3 were not affected by LPS infusion; however, when analyzed as 0 vs. all other doses of LPS combined, there was a tendency for plasma 1,25-(OH)2 vitamin D3 concentration to decrease when cows were infused with LPS. The inflammatory response elicited by LPS altered plasma macromineral concentrations, a result that may have important implications for calcium homeostasis and metabolic health of lactating dairy cows.
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PMID:Effect of lipopolysaccharide infusion on serum macromineral and vitamin D concentrations in dairy cows. 1467 73

Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is a type II C-type lectin that functions as an adhesion receptor and mediates binding and internalization of pathogens such as virus (human immunodeficiency virus, hepatitis C), bacteria (Mycobacterium), fungi, and parasites. DC-SIGN expression in vivo is primarily restricted to interstitial dendritic cells (DC) and certain tissue macrophages. We now report that leukemic THP-1 cells, widely used as a model for monocyte-macrophage differentiation, express very low basal levels of DC-SIGN and that DC-SIGN expression in THP-1 cells is regulated during differentiation. Differentiation-inducing agents (phorbol ester, bryostatin) conveyed THP-1 cells with the ability to up-regulate DC-SIGN mRNA levels and cell surface expression in response to interleukin-4 (IL-4) or IL-13. DC-SIGN up-regulation required a functional JAK-STAT signaling pathway, was inhibited in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha), and conferred THP-1 cells with increased pathogen recognition and T cell stimulatory capabilities. The up-regulation of DC-SIGN on THP-1 cells resembles its inducible expression on monocytes and macrophages, where DC-SIGN expression is also induced by IL-4/IL-13 and negatively regulated by TNF-alpha, LPS, and vitamin D(3). These results point to THP-1 cells as a useful cellular system to characterize the pathogen-binding capabilities of DC-SIGN and to dissect the molecular mechanisms that control its regulated and tissue-specific expression in myeloid dendritic cells, and the results suggest that DC-SIGN constitutes a marker for both DC and alternatively activated macrophages.
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PMID:Regulated expression of the pathogen receptor dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin in THP-1 human leukemic cells, monocytes, and macrophages. 1507 Sep 1


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