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)

5-Halo-6-phenyl pyrimidinones, represented by 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and 2-amino-5-iodo-6-phenyl-4(3H)-pyrimidinone (AIPP), and 8-substituted guanosines, represented by 8-bromoguanosine (8-BrGuo) and 8-mercaptoguanosine (8-MGuo), are well-documented biological response modifiers. We have found that these substituted pyrimidinones and guanosines are very similar in their abilities to activate B cells. ABPP, AIPP, 8-BrGuo, and 8-MGuo induced murine B cells to polyclonally proliferate and differentiate in vitro. The maximal B-cell response levels and the kinetics of the responses elicited with both classes of compounds were comparable; however, ABPP and AIPP were approximately 10-fold more potent than 8-BrGuo and 8-MGuo. An additional similarity observed between the two classes was that polyclonal activation of B cells by ABPP, AIPP, 8-BrGuo, and 8-MGuo was limited to large B cells which had probably been activated previously in vivo. This is in contrast to lipopolysaccharide which is capable of inducing both large, activated B cells and small, resting B cells to proliferate and differentiate. Although substituted pyrimidinones and guanosines were not able to induce new DNA synthesis or antibody production in small B cells, both classes of compounds increased the expression of Ia antigens on the surface of both small and large B cells. These data, together with the recent observations that 8-BrGuo, like ABPP and AIPP, can stimulate NK and cytotoxic macrophage activity via the induction of interferon, strongly suggest that 5-halo-6-phenyl pyrimidinones and 8-substituted guanosines belong to the same structural class of biological response modifiers. Thus, the residues held in common by these two classes of stimulators may interact with the same cellular constituent in the target cells.
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PMID:5-Halo-6-phenyl pyrimidinones and 8-substituted guanosines: biological response modifiers with similar effects on B cells. 325 7

Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.
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PMID:Cytokine induction in mice by the immunomodulator imiquimod. 750 69

Microglia were successfully cultured from human brain tissue from normal and neurologically diseased cases obtained 3.5-10 hours postmortem. Final cell preparations were more than 99% pure as judged by latex bead phagocytosis, expression of microglial phenotypic markers, and absence of astrocytic markers. The expression of complement genes C1qB, C3, and C4 as well as genes for interleukin-(IL-)1 alpha, IL-1 beta, IL-6, tumor necrosis factor (TNF)alpha, IL-1 receptor antagonist, and transforming growth factor beta, but not inducible nitric oxide synthase, by these cells was detected by polymerase chain reaction (PCR) analysis. The pattern of gene expression was evaluated following stimulation of the cells with lipopolysaccharide, phorbol myristate acetate, gamma interferon, and beta amyloid peptide. There was considerable variation in gene response to these activating agents. However, it was of interest that beta-amyloid peptide (1-40) increased the expression of IL-1 beta mRNA in these cells. The number of cases in this study was too small to permit evaluation of microglial response according to the disease state, but the results demonstrate the potential for such studies in the future.
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PMID:Complement and cytokine gene expression in cultured microglial derived from postmortem human brains. 761 8

In Alzheimer disease, a combination of genetic predisposition and environmental factors may contribute to changes in beta-amyloid precursor protein (APP) expression, beta-amyloid peptide deposition, and neuronal loss. Factors such as head injury or acute infection that trigger inflammatory processes may play a crucial role in development of the disease. In the present in vivo study, we showed that, in mouse brain, peripheral stimulation with lipopolysaccharide (LPS) induced a transient increase in the inflammatory cytokine mRNAs (interleukin 1 beta and interleukin 6), followed by changes in expression of APP isoforms in the cerebellum but not in the cerebral cortex. These changes consisted of a decrease in the APP-695 and an increase in the Kunitz protease inhibitor-bearing isoforms (KPI-APP). In the cerebellum of the staggerer mouse mutant, where a severe loss of Purkinje and granule cells occurs, basal mRNA levels of these interleukins were elevated and an increase in the KPI-APP/APP-695 ratio compared to wild-type mice was observed. These abnormalities were further accentuated by LPS stimulation. This study shows that acute and chronic inflammatory processes play an important role in changes in APP expression possibly associated with neurodegeneration.
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PMID:Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. 770 69

In an effort to unravel some of the cellular actions of beta-amyloid protein (A beta), we investigated its effects on interleukin-8 (IL-8) production from human monocytes. Supernatants harvested from cultured monocytes stimulated with the neurotoxic fragment 25-35 of beta-amyloid [A beta(25-35)] contained significant amounts of IL-8. Northern blot analysis demonstrated that A beta(25-35) also induced IL-8 mRNA accumulation. The effect of A beta(25-35) on IL-8 mRNA accumulation and secretion was not mimicked by a scrambled A beta(25-35) peptide, and was not affected by polymyxin B sulphate, which, on the other hand, almost completely abolished the effect of lipopolysaccharide. Our results uncover a new biological action of beta-amyloid: that of stimulating the production of a chemokine from monocytes.
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PMID:beta-Amyloid(25-35) induces the production of interleukin-8 from human monocytes. 779 18

beta-Amyloid protein (betaAP) deposition is a neuropathologic hallmark of Alzheimer's disease (AD). Yet, the source of cerebral betaAP in AD is controversial. We examined the production of betaAP by the BV-2 immortalized microglial cell line using a sensitive enzyme immunoassay. Constitutive production of betaAP was detected in conditioned media from unstimulated BV-2 cells. Further, production of betaAP was induced by treatment of cultures by lipopolysaccharide (LPS) or betaAP-(25-35) and was inhibited by the calpain protease inhibitor MDL 28170. Treatment of BV-2 cells with LPS or betaAP-(25-35) did not affect cell-associated beta-amyloid precursor protein levels. These findings suggest that microglia may be an important source of betaAP in AD, and that microglial production of betaAP may be augmented by proinflammatory stimuli or by betaAP itself.
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PMID:Beta-amyloid peptide secretion by a microglial cell line is induced by beta-amyloid-(25-35) and lipopolysaccharide. 866 28

Attenuating beta-amyloid precursor protein (beta-APP) gene expression may have relevance in diseases such as Alzheimer's disease, where beta-APP has been implicated in neuropathological processes. We report here on the transcriptional down-regulation of beta-APP by interferon-gamma (IFN-gamma) in SKNMC human neuroblastoma cells. Treatment of the cells with IFN-gamma resulted in a 85% dose-dependent inhibition of beta-APP promoter activity after 24 h of exposure, with no changes observed at 5 h. For comparison, additional cytokines and signaling agents were also investigated for effects on beta-APP promoter activity. Elevated levels of activity were observed after treatment with phorbol 12-myristate 13-acetate and basic fibroblast growth factor whereas no significant effects were seen after treatment with lipopolysaccharide or interleukin-1 beta. Thus, IFN-gamma was shown here to be a suppressor of beta-APP promoter activity and is the first cytokine reported to possess such down-regulating effects.
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PMID:Transcriptional inhibition of the beta-amyloid precursor protein by interferon-gamma. 869 21

Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of beta-amyloid peptide (A beta) is one of its main pathological features. In this study we investigated the interaction of human monocyte-like cells with synthetic beta-amyloid peptide A beta (1-40) and its subfragment A beta (25-35). THP-1 cells (a transformed human monocyte cell line) were used with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necrosis factor-alpha (TNF-alpha). First, it was shown that THP-1 cells could be induced to secrete significant amounts of TNF-alpha by interleukin-1, lipopolysaccharide, interferon-gamma (IFN-gamma) and PMA alone or in combination with each other. Next it was shown that A beta (1-40) could also induce secretion of TNF-alpha by THP-1 cells, but the effect was diminished when this peptide was applied in combination with IFN-gamma. The A beta subfragment A beta (25-35) was ineffective in inducing TNF-alpha production. The cellular action of A beta (1-40) appears to involve protein kinase C since pretreatment of THP-1 cells by PMA or the protein kinase C inhibitor H-7 diminished the cellular response to A beta (1-40). Identification of the pathway by which extracellular A beta activates the intracellular PKC-dependent secretion of TNF-alpha may help in developing new therapeutic strategies for Alzheimer's disease.
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PMID:Interaction of Alzheimer beta-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha. 904 34

Cells of the monocyte phagocytic system can generate superoxide and glutamate anions, both of which are neurotoxic at high levels. We used rat peritoneal macrophages as a model system to test the effects of various stimulants on the production of these molecules. Glutamate production by such cells was enhanced, in a concentration-dependent manner, by treatment with serum-opsonized zymosan (OZ), lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and beta-amyloid peptide Abeta (1-40); but not by treatment with the reverse Abeta (40-1) or the Abeta (25-35) subfragment. Superoxide anion production by the cells was stimulated by OZ, PMA, Abeta (1-40), and Abeta (25-35). Moreover, Abeta and its subfragment, when used as priming agents, also enhanced the stimulatory effect of PMA. However, they did not act as priming agents for OZ, suggesting a competition for receptors or intracellular signaling pathways linked to those receptors. Inflammatory mediators, including Abeta, could place glutamate-sensitive neurons at risk by enhancing glutamate and oxygen free radical production by monocyte-derived cells. Such mechanisms could contribute to the pathogenesis of neurodegenerative disorders, including Alzheimer's disease.
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PMID:beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate. 927 45

Glutamate, an excitatory neurotransmitter, is neurotoxic at high concentrations. Neuroglial cells, including astrocytes and microglia, play an important role in regulating its extracellular levels. Cultured human monocytic THP-1 cells increased their glutamate secretion following 18 and 68 h exposure to the inflammatory mediators zymosan, phorbol myristate acetate (PMA), lipopolysaccharide, interferon-gamma, tumor-necrosis factor-alpha and interleukin-1beta. Cultured astrocytoma U-373 MG cells increased their glutamate secretion following similar exposure to zymosan and PMA. DL-Alpha-aminopimelic acid, an inhibitor of the glutamate secretion system, reduced extracellular glutamate in both cell culture systems, while the high-affinity glutamate uptake inhibitors D-Aspartic acid, DL-threo-beta-hydroxyaspartic acid and L-trans-pyrrolidine-2,4-dicarboxylic acid increased extracellular glutamate in U-373 MG, but not THP-1 cell cultures. In co-cultures of THP-1 and U-373 MG cells, extracellular glutamate levels were increased significantly by the Alzheimer beta-amyloid peptide (1-40) and were decreased significantly by the anti-inflammatory drug dexamethasone. These data indicate that inflammatory stimuli may increase extracellular glutamate while antiinflammatory drugs decrease it.
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PMID:Regulation of glutamate in cultures of human monocytic THP-1 and astrocytoma U-373 MG cells. 930 40


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