Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many effects of lipopolysaccharide (LPS) on gene expression, including that of human immunodeficiency virus (HIV), in monocytic cells are mediated by activation of kappa B DNA-binding proteins. However, the specific members of the NF-kappa B/Rel transcription factor family involved in the LPS response, and the mechanisms through which LPS-generated signals are transduced remain unclear. Here we show that LPS induces nuclear expression of c-Rel/p50 heterodimers as well as p50/p65 (NF-kappa B) kappa B DNA-binding complexes in human monocytic THP-1 cells. Nuclear localization of these proteins occurred concomitantly with a rapid decrease in their cytosolic levels and was independent of phorbol ester-sensitive protein kinase C. Within 24 h following LPS stimulation there was a striking increase in the levels of c-Rel, p105, and p50 in the cytosol. The increased levels of these proteins correlated with increases in the amounts of their mRNAs during LPS activation of THP-1 cells. LPS activation of THP-1 cells resulted in phosphorylation of MAD3 (an I kappa B-like protein), a rapid increase in MAD3 mRNA, and an increase in MAD3 protein by 2 h. Thus, LPS activation of human monocytic cells results in nuclear expression of c-Rel/p50 and p50/p65 (NF-kappa B) and induces phosphorylation of MAD3.
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PMID:Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells. 850 9

Cationic liposomes may be valuable for the delivery of anti-sense oligonucleotides, ribozymes, and therapeutic genes into human immunodeficiency virus type 1 (HIV-1)-infected and uninfected cells. We evaluated the toxicity of three cationic liposomal preparations, Lipofectamine, Lipofectin, and 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE) reagent, to HIV-infected and uninfected cells. Monocyte/macrophages were infected with HIV-1BaL and treated with liposomes in medium containing 20% fetal bovine serum (FBS) for 4 h or 24 h at 37 degree C. Uninfected monocytic THP-1 cells and chronically infected THP-1/HIV-1IIIB cells were treated with phorbol 12-myristate 13-acetate (PMA) and exposed to liposomes in the presence of 10% FBS. Toxicity was evaluated by the Alamar Blue assay and viral p24 production. The toxic effect of cationic liposomes was very limited with uninfected cells, although concentrations of liposomes that were not toxic within a few days of treatment could cause toxicity at later times. In HIV-1BaL-infected macrophages, Lipofectamine (up to 8 microM) and Lipofectin (up to 40 microM) were not toxic after a 4-h treatment, while DMRIE reagent at 40 microM was toxic. While a 4-h treatment of THP-1/HIV-1IIIB cells with the cationic liposomes was not toxic, even up to 14 days post-treatment, all three cationic liposomes were toxic to cells at the highest concentration tested after a 24-h treatment. Similar results were obtained with the Alamar Blue assay, Trypan Blue exclusion and a method that enumerates nuclei. Infected cells with relatively high overall viability could be impaired in their ability to produce virions, indicating that virus production appears to be more sensitive to treatment with the cationic liposomes than cell viability. Our results indicate that HIV-infected cells are more susceptible than uninfected cells to killing by cationic liposomes. The molecular basis of this differential effect is unknown; it is proposed that alterations in cellular membranes during virus budding cause enhanced interactions between cationic liposomes and cellular membranes.
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PMID:Human immunodeficiency virus type-1 (HIV-1) infection increases the sensitivity of macrophages and THP-1 cells to cytotoxicity by cationic liposomes. 870 87

The long terminal repeat (LTR) of human immunodeficiency virus type 1 (HIV-1) contains sequences required for the initiation of gene transcription. Among the substances known to activate the HIV-1 LTR is hydrogen peroxide (H2O2). We report here that H2O2-induced activation of the LTR in the macrophage cell line THP-1 and the lymphocyte cell line, Jurkat, is greatly increased by vanadate. Activation of the LTR by phorbol myristate acetate, tumor necrosis factor alpha, lipopolysaccharide, or Staphylococcus epidermidis extract was not increased by vanadate, indicating some selectivity for H2O2. H2O2 and vanadate also acted synergistically to increase the production of HIV-1 virions by the latently infected macrophage cell line U-1 as determined by p24 antigen release and the detection of intact virions by electron microscopy. Effects were observed at H2O2 and vanadate concentrations down to 3 x 10(-6) M, with high concentrations leading to cell toxicity. Catalase was strongly inhibitory when added prior to the interaction of H2O2 and vanadate, but was considerably less inhibitory when the H2O2 and vanadate were allowed to preincubate prior to the catalase addition. H2O2 reacts with vanadate to form peroxides of vanadate that have potent biological effects. Our findings suggest that among these is the activation of the HIV-1 LTR.
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PMID:Activation of the HIV long terminal repeat and viral production by H2O2-vanadate. 872 29

There is increasing evidence that lipoproteins of Treponema pallidum and Borrelia burgdorferi are key inflammatory mediators during syphilis and Lyme disease. A principal objective of the present study was to identify more precisely similarities and divergences among lipopolysaccharide (LPS)- and lipoprotein-lipopeptide-induced immune cell signaling events. Like LPS, purified native B. burgdorferi OspA and synthetic analogs of OspA, OspB, and two T. pallidum lipoproteins (Tpp47 and Tpp17) all induced NF-kappa B translocation in THP-1 human monocytoid cells. Acylation of OspA and the synthetic peptides was requisite for cell activation. Polymyxin B abrogated only the response to LPS. By using 70Z/3-derived pre-B-cell lines either lacking or expressing human CD14 (the LPS receptor), it was observed that expression of human CD14 imparted responsiveness to LPS but not to OspA or spirochetal lipopeptides (assessed by induction of NF-kappa B and expression of surface immunoglobulin M). Finally, the biological relevance of the observation that T. pallidum lipoproteins-lipopeptides induce both NF-kappa B and cytokine production in monocytes was supported by the ability of the synthetic analogs to promote human immunodeficiency virus replication in chronically infected U1 monocytoid cells; these observations also suggest a potential mechanism whereby a syphilitic chancre can serve as a cofactor for human immunodeficiency virus transmission. The combined data lend additional support to the proposal that spirochetal lipoproteins and LPS initiate monocyte activation via different cell surface events but that the signaling pathways ultimately converge to produce qualitatively similar cellular responses.
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PMID:Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-kappa B. 875 37

We have previously demonstrated that the membrane of the Staphylococcus aureus L form induced tumor necrosis factor alpha (TNF-alpha) from murine macrophages. In this study, we purified two proteins which induce TNF-alpha production from a human monocytic cell line, THP-1, and murine macrophages. These molecules were purified from delipidated membranes by deoxycholic acid extraction, two-step anion-exchange chromatography, and preparative electrophoresis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified proteins showed for each a single band with a molecular mass of 30, and 36 kDa. These proteins were heat stable. Polymyxin B did not affect the production of TNF-alpha induced by these proteins. Furthermore, these proteins induced comparable levels of TNF-alpha in both lipopolysaccharide-responsive and -nonresponsive mouse macrophages. Pretreatment of murine macrophages with gamma interferon enhanced 30- and 36-kDa protein-mediated TNF-alpha production. The 30-kDa protein showed lethal toxicity to D-galactosamine-treated mice. The 30- and 36-kDa proteins stimulated the human immunodeficiency virus type 1 long terminal repeat in a monocytic cell line but not a T-cell line. This effect appeared to be mediated through the induction of nuclear factor kappaB. These results indicate that the 30- and 36-kDa proteins, membrane constituents of the S. aureus L form, may play a role in S. aureus infection and/or in human immunodeficiency virus type 1-infected individuals.
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PMID:Proteins of 30 and 36 kilodaltons, membrane constituents of the Staphylococcus aureus L form, induce production of tumor necrosis factor alpha and activate the human immunodeficiency virus type 1 long terminal repeat. 875 63

Knowledge of CD4 conformation within the membranes of human lymphoid and monocytoid cells is essential for a clear understanding of its function as a ligand for major histocompatibility complex II (MHC) molecules in T cell activation and for gp120 in human immunodeficiency virus (HIV) infection. The charge and structure of native (nCD4) and soluble recombinant CD4 (rCD4) were examined by one- and two-dimensional (2-DE) electrophoresis antigen mapping and silver staining. Recombinant CD4 was partitioned by nonequilibrium pH gradient electrophoresis (NEPHGE) and revealed a number of differentially charged 44 kDa species (pI > 9.5). Biotinylation (4 h, room temperature) of rCD4 yielded a single labelled species on sodium dodedyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with an increased apparent molecular mass to 50 kDa, consistent with a maximal incorporation of approximately 18 molecules of biotin per rCD4 molecule. The milder biotinylation (15 min, 4 degrees C) of cell-(CEM-T4, THP-1) expressed CD4 was not accompanied by any apparent alteration in molecular weight, nor abrogation of CD4 antigenicity. This was determined by isolation of nCD4 by immunoprecipitation and SDS-PAGE immunoblotting, using anti-CD4 mAbs (leu3a, OKT4A, Q4120, T4, OKT4, Q425) and by flow cytometry (leu4a, T4). The immunoprecipitation of full-length native CD4 from lymphoid MT2 and CEM-T4 cell extracts, however, revealed both monomeric and higher-order CD4 antigen complexes by immunoblotting. These studies describe the biotinylation, 1-DE and 2-DE of CD4 preparations, and indicate the capacity of CD4 of lymphocytes to form complexes which may influence CD4 conformation and epitope availability.
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PMID:Analysis of recombinant and native CD4 by one- and two-dimensional gel electrophoresis. 890 46

Gene expression of human immunodeficiency virus (HIV) depends on a host cellular transcription factors including nuclear factor-kappaB (NF-kappaB). The involvement of reactive oxygen intermediates (ROI) has been implicated as intracellular messengers in the inducible activation of NF-kappaB. In this study, we compared the efficacy of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), which are widely recognized NF-kappaB inhibitors. Here, we demonstrate that LA has a more potent activity in inhibiting NF-KappaB-mediated gene expression in THP-1 cells that have been stably transfected with a plasmid bearing a hygromycin B resistance gene under the control of HIV-1 long terminal repeat (LTR) promoter. The spontaneous activation of NF-kappaB in this cell culture system leads to expression of the hygromycin phosphotransferase gene hence rendering the cells resistance to hygromycin B. In this study, the effect of the test compounds against transcriptional activity of HIV-1 LTR was evaluated based on the degree of cellular toxicity due to the inhibitory activity on the expression of hygromycin B resistance gene in the presence of hygromycin B. We also found that 0.2 mM LA could cause 40% reduction in the HIV-1 expression from the TNF-alpha-stimulated OM 10.1, a cell line latently infected with HIV-1. On the other hand, 10 mM NAC was required to elicit the same effect. Furthermore, the initiation of HIV-1 induction by TNF-alpha was completely abolished by 1 mM LA. These findings confirm the involvement of ROI in NF-kappaB-mediated HIV gene expression as well as the efficacy of LA as a therapeutic regimen for HIV infection and acquired immunodeficiency syndrome (AIDS). Moreover, this study validates the applicability of our present assay system which we primarily designed for the screening of candidate drugs against HIV-1 gene expression.
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PMID:Alpha-lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants. 892 35

The activity against Toxoplasma gondii of 2',3' dideoxyinosine (ddI), an anti-human immunodeficiency virus drug, was examined in an in vitro and in vivo study. Cell cultures infected with a strain known to cause chronic infections were used to show the dose-dependent effect of this drug compared with spiramycin and sulfadiazine. When a dose of 4 microg/ml was used, no infected THP-1 cells or parasites were found after 60 h of incubation. An electron-microscopic study confirmed that after 12 h at 1 microg/ml, the few parasites observed were severely altered. The treatment of chronically infected mice 3 months postinfection showed that a 30-day treatment with 2 mg of ddI/ml induced a significant reduction in the number of T. gondii cysts in the cerebral tissue. These cysts were not viable, as confirmed by immunofluorescence and reinfection experiments. These experiments suggest a possible role for ddI in the treatment of toxoplasmosis, and this possibility deserves further investigation.
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PMID:Effects of 2',3'-dideoxyinosine on Toxoplasma gondii cysts in mice. 921 Jun 79

Because candidiasis and cryptococcosis are common in human immunodeficiency virus (HIV)-infected persons, the effect of Cryptococcus neoformans and Candida albicans on HIV expression in monocytic cells was examined. Stimulation of the latently HIV-infected myelomonocytic cell line OM-10.1 with C. neoformans and C. albicans in the presence of pooled human serum caused a ratio-dependent increase in HIV production. Induction of HIV by C. neoformans was enhanced by anti-capsular antibody, while induction by both organisms was inhibited by anti-TNF-alpha antibody. In THP-1 cells transfected with HIV plasmid constructs, both organisms induced transcription from the HIV long terminal repeat that was dependent on intact NF-kappaB binding sequences. Thus, C. neoformans and C. albicans enhance HIV expression in monocytic cells through a TNF-alpha- and NF-kappaB-dependent mechanism. In HIV-infected patients, such enhancement may further impair host immunity and could accelerate the course of HIV disease.
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PMID:Induction of human immunodeficiency virus type 1 expression in monocytic cells by Cryptococcus neoformans and Candida albicans. 923 16

Human CC chemokine receptor 5 (CCR5), mediates the activation of cells by the chemokines macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and RANTES, and serves as a fusion cofactor for macrophage-tropic strains of human immunodeficiency virus type 1. To understand the molecular mechanisms that regulate human CCR5 gene expression, we initiated studies to determine its genomic and mRNA organization. Previous studies have identified a single CCR5 mRNA isoform whose open reading frame is intronless. We now report the following novel findings. 1) Complex alternative splicing and multiple transcription start sites give rise to several distinct CCR5 transcripts that differ in their 5'-untranslated regions (UTR). 2) The gene is organized into four exons and two introns. Exons 2 and 3 are not interrupted by an intron. Exon 4 and portions of exon 3 are shared by all isoforms. Exon 4 contains the open reading frame, 11 nucleotides of the 5'-UTR and the complete 3'-UTR. 3) The transcripts appear to be initiated from two distinct promoters: an upstream promoter (PU), upstream of exon 1, and a downstream promoter (PD), that includes the "intronic" region between exons 1 and 3. 4) PU and PD lacked the canonical TATA or CAAT motifs, and are AT-rich. 5) PD demonstrated strong constitutive promoter activity, whereas PU was a weak promoter in all three leukocyte cell environments tested (THP-1, Jurkat, and K562). 6) We provide evidence for polymorphisms in the noncoding sequences, including the regulatory regions and 5'-UTRs. The structure of CCR5 was strikingly reminiscent of the overall structure of other chemokine/chemoattractant receptors, underscoring an important evolutionarily conserved function for a prototypical gene structure. This is the first description of functional promoters for any CC chemokine receptor gene, and we speculate that the complex pattern of splicing events and dual promoter usage may function as a versatile mechanism to create diversity and flexibility in the regulation of CCR5 expression.
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PMID:The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5'-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons. 938 1


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