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)

Macrophages play an important role in the control of and resistance to Entamoeba histolytica (E. histolytica). However, E. histolytica infections are characterized by suppression of cell-mediated immunity. To elucidate the molecular mechanisms whereby amoebae modulate host defences, we investigated whether the parasite elicits the 'immediate early' gene c-fos and cytokine tumour necrosis factor-alpha (TNF)-alpha mRNA and determined the signal transduction pathways involved in naive bone marrow-derived macrophages (BMM). E. histolytica stimulated a rapid and transient expression of c-fos and low levels of TNF-alpha mRNA, whereas the non-pathogenic Entamoeba moshkovshii (E. moshkovskii) did not. Inhibition of the protein kinase C (PKC) pathway with the pharmacological inhibitor H7 and by PKC depletion with phorbol myristate acetate showed that E. histolytica modulates TNF-alpha and c-fos gene expression through a PKC-dependent stimulus-response coupling event. E. histolytica activated and translocated PKC to the membrane fraction in BMM demonstrating a rapid and direct effect on PKC enzyme activity. Unlike lipopolysaccharide (LPS), BMM stimulated with E. histolytica had reduced stability of both c-fos and TNF-alpha mRNA transcripts (> 50%) and failed to secrete TNF-alpha protein. BMM treated with amoebic proteins and stimulated with LPS, or interferon-gamma (IFN-gamma)+LPS, resulted in a 33% and 50% reduction in TNF-alpha mRNA levels, respectively. These data argue that although E. histolytica stimulates c-fos and TNF-alpha gene expression through PKC signal transduction, the rapid degradation of the mRNAs, the lack of secreted TNF-alpha protein and the observed decreased responsiveness to a stimulatory signal may be a novel mechanism whereby the parasite modulates host defence mechanisms.
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PMID:Entamoeba histolytica stimulates the unstable transcription of c-fos and tumour necrosis factor-alpha mRNA by protein kinase C signal transduction in macrophages. 759 Aug 81

The expression of cytokine genes for interleukin-1 (IL-1) (alpha and beta) and tumour necrosis factor-alpha (TNF-alpha), along with the proto-oncogenes c-fos, c-fms and c-myc, was examined by nuclear run-off and Northern blot analysis during in vitro differentiation of colony-stimulating factor type-1 (CSF-1)-derived bone marrow macrophages (BMDM). Constitutive transcription of c-myc was maximal on day 3 and decreased with differentiation. Constitutive transcription of c-fms and c-fos was similar at all times examined. In contrast, the steady-state mRNA levels were maximal on day 5 for c-myc and day 7 for c-fms and c-fos. Thirty minutes after endotoxin (lipopolysaccharide; LPS) stimulation, there was a rapid increase in run-off transcription rates for c-myc in day 3-day 9 BMDM, with maximal levels observed in day 7 BMDM. c-fms transcription was maximally induced within 1 hr by LPS in day 3 and day 5 BMDM. LPS induced transcription of c-fos to equivalent levels in day 3-day 9 BMDM. LPS stimulation augmented steady-state mRNA levels for c-myc, c-fms and c-fos. Maximal induction of c-myc was observed in day 3 BMDM. c-fos and c-fms were both maximally induced in day 5 and day 7 BMDM. Interferon-gamma (IFN-gamma) had no effect on transcription of the proto-oncogenes examined. In contrast to the proto-oncogenes, peak levels of run-off transcription for IL-1 alpha and IL-1 beta genes were observed 1-2 hr after LPS stimulation for day 3, day 5 and day 7 BMDM. The kinetics of LPS-induced steady-state mRNA accumulation of IL-1 alpha and IL-1 beta were similar to the kinetics of run-off transcription. Constitutive transcription of TNF-alpha was observed on all days of differentiation. LPS and IFN-gamma both enhanced run-off transcription of the TNF-alpha gene; however, LPS had a more pronounced effect. The kinetics of induction of TNF-alpha transcription paralleled the kinetics of steady-state TNF-alpha mRNA accumulation. IFN-gamma resulted in secretion of TNF-alpha in day 5, day 7, and day 9 BMDM after 4-8 hr of stimulation. Day 3 BMDM had little, if any, secreted TNF-alpha activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endotoxin and interferon-gamma differentially regulate the transcriptional levels of proto-oncogenes and cytokine genes during the differentiation of colony-stimulating factor type-1-derived macrophages. 764 23

We examined effects of deregulated c-fos on the proliferation and differentiation of B cells in vitro, using splenic B cells from H2-c-fos transgenic mice. When these cells were cultured with lipopolysaccharide (LPS) plus recombinant interleukin 4 (rIL-4) (10(4) U/ml), the proliferative response of the B cells was augmented with any dose of LPS used. This augmented proliferation resulted in an increase in IgG1 production in the culture, at the lower concentrations of LPS (< 2.5 micrograms/ml). However, H2-c-fos B cells did not produce IgG1 in the culture at higher concentrations of LPS (> 5 micrograms/ml) probably due to the perturbation of B cell differentiation to antibody-forming cells. These results suggest that the deregulated expression of c-fos modulates the proliferation and differentiation of B cells stimulated with LPS plus rIL-4.
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PMID:Deregulated c-fos modulates B cell responses to switch mediators. 768 62

Macrophages (M phi)3 function by a two-step process that includes priming (induction of cytokine and enzyme mRNA) and activation (production of effector molecules). The initial steps in M phi priming involve the expression of certain proto-oncogenes that regulate expression of other genes. Because tumor growth primes M phi to produce several suppressor monokines, we determined if cancer induced M phi expression of these proto-oncogenes. Unstimulated peritoneal M phi from tumor-bearing hosts (TBH) constitutively expressed the proto-oncogenes c-fms, c-fos, c-myc, and c-myb, whereas normal host (NH) M phi had little or no expression of these proto-oncogenes. When M phi were given a 24-h adherence priming stimulus, NH M phi expressed c-fms and c-fos at levels equivalent to TBH M phi constitutive expression. Adherence had little or no effect on c-fms and c-fos expression in TBH M phi or on NH and TBH M phi c-myc expression. c-myb expression was not induced in NH M phi during adherence and was strongly decreased in TBH M phi. Activation with a 1-h lipopolysaccharide-treatment increased NH and TBH M phi expression of c-fms, c-fos, and c-myc, with higher expression of these proto-oncogenes in TBH M phi. Activation failed to induce c-myb expression in NH M phi and completely inhibited expression in TBH M phi. Because c-fms, c-fos, and c-myc are normally expressed early during M phi activation, our results suggest that tumor growth primes M phi by inducing expression of these proto-oncogenes. c-myb is expressed in immature M phi and is downregulated during M phi activation. These observations explain why NH M phi expression of c-myb was not induced and are consistent with reports that suggest TBH M phi have not reached full developmental maturity. The induction of M phi proto-oncogene expression during cancer may put M phi in a primed state, which leads to earlier and stronger production of adverse suppressor and cytotoxic molecules.
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PMID:Macrophage priming and activation during fibrosarcoma growth: expression of c-myb, c-myc, c-fos, and c-fms. 785 63

Previous studies demonstrated that the intraperitoneal injection of epidermal growth factor (EGF) into mice resulted in the appearance, within minutes, of several tyrosine-phosphorylated proteins in liver nuclei. Two of these proteins have been identified as the transcription factors p91/p84 (Stat1 alpha/1 beta) (Ruff-Jamison, S., Chen, K., and Cohen, S. (1993) Science 261, 1733-1736). We have now identified, by Western blotting and immunoprecipitation, an additional EGF-modulated transcription factor, Stat3. We find that Stat3 is tyrosine-phosphorylated and present in mouse liver nuclei following either EGF or lipopolysaccharide administration. Gel shift analyses show that Stat3 is capable of specifically binding the SIE (a DNA sequence present in the c-fos promoter). Three active SIE binding complexes (SIF A, B, and C) exist in the nucleus after the administration of EGF: one complex that contains Stat3, one that contains Stat1, and a third complex that appears to contain both proteins. Only one active SIE binding complex, containing Stat3, was detected after the administration of lipopolysaccharide.
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PMID:Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. 807 11

Activation of monocytes by bacterial lipopolysaccharides (LPSs) is a central component in the pathogenesis of septic shock syndrome. Interleukin 10 (IL-10) is a potent monocyte-deactivating factor and transcriptionally inhibits LPS-induced expression of proinflammatory mediators. The intracellular signaling pathways of LPS have been only partially characterized and mechanisms of IL-10 signaling remain unknown. We show that LPS activates the protein tyrosine kinase (PTK) p56lyn and that this is associated with tyrosine phosphorylation of the protooncogene product Vav. These events are completely blocked by the tyrosine kinase inhibitor herbimycin A. LPS also increases Ras activation in monocytes. LPS-triggered phosphorylation of mitogen-activated protein kinase is a downstream activation event that is also reduced by herbimycin A. Analysis of the IL-10 effects shows that it completely inhibits the p56lyn tyrosine kinase activation and all other subsequent events in this pathway including Ras activation. The IL-10 effects are selective since it reduced PTK-dependent cytokine mRNA expression but not the PTK independent induction of c-jun and c-fos mRNA in LPS-activated monocytes. These results identify the Ras signaling pathway as a component of intracellular signaling in LPS-stimulated monocytes and define early events in this response as targets of monocyte deactivation by IL-10.
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PMID:Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway. 807 29

We and others have reported that c-fos protein is induced in the hypothalamus and brain stem of the rat following central and peripheral injections of endotoxin (lipopolysaccharide; LPS). We have now examined possible mechanisms through which LPS induces c-fos protein. The cyclooxygenase inhibitor indomethacin and the glutamate NMDA antagonist MK801 inhibited c-fos protein in the paraventricular nucleus (PVN), supraoptic nucleus (SON), and the A1/A2 regions of the brain stem induced by IP or IV injections of LPS (40 micrograms). The H1 histamine antagonist diphenhydramine, but not the H2 histamine antagonist cimetidine, reduced the amount of c-fos labeling. MK801 also attenuated the effects of stress (foot shock) on c-fos protein; however, indomethacin had no effect on c-fos protein induced by stress. We next examined the importance of visceral afferent innervation on the response to LPS or stress. Subdiaphragmatic vagotomy completely blocked the induction of c-fos protein following IP injections of LPS; however, vagotomy had a minimal effect on c-fos protein induced in the PVN and SON following IV injections of LPS, but potentiated c-fos induction following foot shock. Thus, prostaglandin synthesis, glutamate release, histamine receptors, and visceral afferents represent functional biochemical and neural pathways through which endotoxin activates c-fos protein in specific autonomic and neuroendocrine regulatory nuclei. Activation of NMDA glutamate receptors may represent a final common pathway for the induction of c-fos protein in the brain induced by both endotoxin and stress.
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PMID:Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. 819 36

The process of tumorigenesis is frequently associated with resistance to growth inhibition by physiological regulators of normal cells. Murine macrophage-like cell lines BAC1.2F5, RAW264, J774.1A and PU5/1.8 were resistant to growth inhibition by bacterial lipopolysaccharide (LPS) and pertussis toxin, agents that blocked growth of primary bone marrow-derived macrophages (BMDM) in the presence of macrophage colony-stimulating factor (CSF-1). The resistance of the CSF-1-dependent cell line BAC1.2F5 to growth inhibition by pertussis toxin argues against the possibility that pertussis toxin-sensitive G proteins are essential for the pathway of growth stimulation by CSF-1. Conversely, these data add further weight to the argument that LPS mediates some of its biological activities by mimicking the action of pertussis toxin and inhibiting G protein function. The resistance of cell lines to LPS and pertussis toxin was not correlated with any alteration in the expression of mRNA encoding any of three pertussis-toxin sensitive G protein alpha subunits. The pattern of G protein expression was consistent between primary cells and tumour cells, suggesting that this is a differentiation marker. In particular, Gi alpha 2 mRNA was expressed at remarkably high levels in all of the cells. The specificity of LPS resistance was investigated by studying down-regulation of CSF-1 binding and induction of protooncogene c-fos and tumour necrosis factor (TNF) mRNA. BAC1.2F5 cells were LPS-resistant in each of these assays. In CSF-1 binding, RAW264 and J774.1A responded in the same way as bone marrow-derived macrophages but required higher doses of LPS, whereas c-fos and TNF mRNA were induced in these cells at concentrations that did not inhibit growth. In PU5/1.8 cells, CSF-1 binding was already very low and was not further down-regulated, but c-fos and TNF mRNA was inducible by LPS. By contrast to primary macrophages, the cell lines did not respond to LPS with down-regulation of c-fms mRNA, which encodes the CSF-1 receptor. Hence, the resistance of macrophage-like tumour cells to LPS and pertussis toxin was specific to the pathways controlling growth, and was correlated with altered regulation of the CSF-1 receptor.
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PMID:The resistance of macrophage-like tumour cell lines to growth inhibition by lipopolysaccharide and pertussis toxin. 821 90

We have examined effects of the deregulated c-fos protein on IgG2b production of B cells cultured with lipopolysaccharide (LPS) using splenic B cells from a transgenic line carrying the mouse c-fos gene under the control of the interferon alpha/beta (IFN) inducible Mx promoter (Mx-c-fosD). High c-fos expression was induced in the Mx-c-fosD B cells during the first two days of culture. DNA synthesis and IgG2b production were augmented in the culture. When IFN was added together with LPS, the high c-fos expression was prolonged until day 3 of culture. IgG2b production was remarkably suppressed. However, the production was not suppressed by upregulation of c-fos via exogenous IFN on day 4 of culture. These results suggest a regulatory effect of the c-fos protein on the differentiation of B cells to IgG2b producing cells at a distinct period.
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PMID:Deregulated c-fos modulates IgG2b production of B cells mediated by lipopolysaccharide. 822 87

The functional neuroanatomy of the immune system link to the CNS was investigated by assessing neuronal activity with Fos immunohistochemistry following systemic lipopolysaccharide (LPS) administration. Two hours after LPS robust Fos-like immunoreactivity (Fos-IR) was observed in several nuclear groups in the brain including the paraventricular and supraoptic nuclei of the hypothalamus, central nucleus of the amygdala, and nucleus of the solitary tract. A similar but diminished pattern of Fos-IR was present at 6 hours and was absent 24 hours after LPS administration. Investigation of the functional neuroanatomy of the acute phase reaction could prove to be critical in enhancing the ability of individuals to combat insults such as tissue damage and inflammation. The central nervous system (CNS), particularly the hypothalamus, is intimately involved in the coordination of the various aspects of the acute phase reaction (reviewed in 1). Understanding the functional neuroanatomy by which the brain responds to immune system challenges would greatly augment the ability to control the deleterious and enhance the beneficial aspects of the acute phase reaction. In this study we have used lipopolysaccharide (LPS or endotoxin) administration as an experimental model to study immune system activation. LPS is a complex glycolipid and a component of the outer membrane of most Gram-negative bacteria (2). Administration of LPS has been demonstrated to induce the secretion of several proteins including interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6; reviewed in 3). Further, it has been hypothesized that LPS induction of IL-1 and TNF is the key event in the pathogenesis of Gram-negative bacterial septic shock syndrome (2). Many recent studies have utilized immunohistochemistry for Fos, the product of the immediate early gene c-fos, as a marker of neuronal activation. Fos is a nuclear-binding protein that is expressed at increased levels in activated neurons (4). Although the exact function of Fos in the CNS is still unknown, it is thought that Fos is transcribed after cellular stimulation as a means to convert a stimulus into long-term genetic action (for reviews see 5,6). This study investigated the activation of the CNS by peripherally administered LPS isolated from the bacterium Pasteurella multocida. As a marker of neuronal activation, immunohistochemistry for the Fos protein was performed and image analysis was utilized to quantify the Fos induction in the CNS.
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PMID:Induction of Fos-like immunoreactivity in the rat brain following Pasteurella multocida endotoxin administration. 824 37


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