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)

To clarify the induction pathway of inducible nitric oxide (NO) synthase in the brain, we examined the effects of interferon-gamma and lipopolysaccharide on the induction of inducible NO synthase in glial cells cultured from neonatal rats, compared to those in the macrophage cell line RAW264.7 which was derived from Abelson leukemia virus-induced BALB/c lymphocytic lymphoma. NO synthase activity (NO2- accumulation) and 130 kDa protein of inducible NO synthase were induced 24 h after treatment with interferon-gamma or lipopolysaccharide in both glial cells and RAW264.7 macrophages. These induction activities were inhibited by a tyrosine kinase inhibitor, herbimycin A. Immunoprecipitation assay using antibodies against Janus kinases, and the signal transducer and activator of transcription-1 (STAT1), revealed that interferon-gamma induced tyrosine phosphorylation of the just another kinase-2 (Jak2) and STAT1 alpha but did not induced the phosphorylation of Jak1, the non-receptor tyrosine kinase-2 (Tyk2) and STAT1 beta. Tyrosine phosphorylation of Jak2 and STAT1 alpha induced by interferon-gamma was also inhibited by herbimycin A, while lipopolysaccharide did not induce any tyrosine phosphorylation of Janus kinases and STAT1 at all. These results suggest that the interferon-gamma-induced inducible NO synthase induction involves activation of Jak2-STAT1 alpha pathway in both glial cells and macrophages.
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PMID:Possible involvement of Janus kinase Jak2 in interferon-gamma induction of nitric oxide synthase in rat glial cells. 881 44

Recent studies have indicated that glial cells such as astrocytes and microglia are activated in an early and delayed episode after brain damage. However, the mechanism and function of glial activation are still unclear. I examined whether the induction of inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1) and major histocompatibility complex (MHC) antigen was involved in the glial activation. The microinjection of interferon-gamma and lipopolysaccharide into rat hippocampus induced MHC class II and iNOS in microglia. The iNOS induction may be involved in the activation of tyrosine kinases and transcription factors such as signal transducer and activator of transcription-1 (STAT1) and nuclear factor-kappa B (NF-kappa B). Subsequently, neuronal cell death occurred in the hippocampus, but cell death was undetectable in both microglia and astrocytes that expressed HO-1. Thus, induction of iNOS and HO-1 in glial cells may be involved in hippocampal neurodegeneration and resistance to oxidative stress in glial cells, respectively. In Alzheimer's disease (AD) brains, iNOS expression was at a very low level, although STAT1 and NF-kappa B were significantly increased. Also, Bcl-2, Bcl-x, Bak, Bad and p53 were increased in AD brains. These observations suggest that oxidative stress and glial activation without iNOS induction may be involved in neurodegeneration of AD brains.
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PMID:[Functional activation of glial cells in early and delayed episodes of the brain damage]. 958 78

Effects of ethanol in vitro on inducible nitric oxide (NO) production in RAW 264.7 macrophages were investigated. Adding ethanol (100-600 mM) to the incubation medium simultaneously with lipopolysaccharide (LPS) concentration-dependently inhibited LPS-induced NO production without being cytotoxic. This inhibitory effect of ethanol on NO production was almost abolished when ethanol was added to the medium 12 h after the start of incubation with LPS, implying that ethanol inhibits the induction of inducible NO synthase (iNOS). Both LPS-induced protein and mRNA expression of iNOS were inhibited by ethanol (100-600 mM) concentration-dependently. LPS-induced activation of signal transducer and activator of transcription-1 (STAT-1) was inhibited by ethanol (100-400 mM). On the other hand, LPS-induced translocation of nuclear factor-kappaB (NF-kappaB) was not affected significantly by 100-600 mM ethanol. When cells were exposed to ethanol for 72 h before LPS stimulation, the inhibitory effect of ethanol on subsequent NO production was significantly attenuated compared with that in control cells pretreated with vehicle for 72 h, suggesting the development of tolerance to the inhibitory action of ethanol. These results suggest that ethanol inhibits inducible NO production, probably by inhibiting STAT1 activation. Tolerance to this inhibitory action of ethanol is produced after chronic exposure.
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PMID:Mechanism of inhibitory action of ethanol on inducible nitric oxide synthesis in macrophages. 1223 42

The regulation of signal transducer and activator of transcription-1 (STAT-1) by cytokines and all-trans-retinoic acid (RA) was investigated in THP-1 monocytic cells cultured with RA and stimulated with lipopolysaccharide (LPS), tumour necrosis factor-alpha (TNF-alpha), interferon-beta (IFN-beta), and IFN-gamma, individually or in combinations. While RA (10(-8) m) alone did not alter STAT-1 activation or expression in THP-1 cells, RA enhanced or prolonged STAT-1 activation (tyrosine 701 phosphorylation) and gene expression (mRNA and protein) induced by either IFN-beta or IFN-gamma. However, in contrast, RA reduced STAT-1 activation and gene expression induced by LPS and/or TNF-alpha by about 50-70%, and lowered in vitro DNA binding activity to both a STAT-1 consensus element and a nuclear factor kappa B (NFkappaB) binding element. These results imply that RA can significantly rebalance STAT-1-dependent responses, and that one of the mechanisms may be through the inhibition of the NFkappaB pathway.
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PMID:Opposing cytokine-specific effects of all trans-retinoic acid on the activation and expression of signal transducer and activator of transcription (STAT)-1 in THP-1 cells. 1238 99

Lipopolysaccharide (LPS) induces neutrophils to synthesize and secrete pro-inflammatory cytokines and chemokines, which are regulated at both the transcriptional and translational level. We reported previously that neutrophils stimulated with LPS induce expression of genes typically expressed in response to stimulation with antiviral type I interferons (IFN), such as myxovirus resistance-1 (MX1). However, we present evidence that this response of neutrophils to lipopolysaccharide occurs in the absence of interferon-dependent signaling. Lipopolysaccharide-stimulated neutrophils do not phosphorylate the interferon-associated transcription factors signal transducer and activator of transcription-1 and -3, and medium from lipopolysaccharide-stimulated cells was unable to induce MX1 gene expression, suggesting a soluble factor is not involved. Furthermore, LPS did not alter expression of IFNA and IFNB genes. In contrast to neutrophils, LPS-stimulated human monocyte-derived macrophages induced the expression of MX1, but IFNB was induced, and medium from LPS-stimulated monocyte-derived macrophages supported MX1 induction. An inhibitor of p38 kinase blocked induction of MX1 by lipopolysaccharide, but not IFNalpha, in neutrophils, and induction of MX1 was dependent on protein synthesis. LPS, but not IFNalpha, substantially activated p38. In contrast, the induction of MX1 by LPS in monocyte-derived macrophages was insensitive to p38 inhibition, although p38 is phosphorylated in LPS-stimulated but not IFNalpha-stimulated monocyte-derived macrophages. The expression of MX1 in neutrophils and monocyte-derived macrophages is mediated by TLR4 but not TLR2. The data presented here indicate that lipopolysaccharide activates novel interferon-independent signaling pathways in neutrophils and that induction of antiviral genes is a consequence of exposure of neutrophils to bacterial products.
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PMID:Lipopolysaccharide stimulates p38-dependent induction of antiviral genes in neutrophils independently of paracrine factors. 1259 30

Baicalein (5,6,7-trihydroxyflavone), a flavonoid originated from the root of Chinese medicinal herb Scutellaria baicalensis, has been shown to exert anti-inflammatory and antioxidant effects, and it is a well known inhibitor of 12-lipoxygenase. We have previously reported that neuroglia undergo nitric oxide (NO)-dependent and NO-independent apoptosis upon inflammatory activation. In the current work, we asked how anti-inflammatory baicalein influences autoregulatory apoptosis of activated microglia and their NO production. Baicalein attenuated NO production and apoptosis of lipopolysaccharide (LPS)-activated, but not interferon-gamma-activated, BV-2 mouse microglial cells as well as rat primary microglia cultures. The inhibition of NO production by baicalein was due to the suppression of inducible NO synthase induction. Moreover, baicalein inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activity in BV-2 cells without affecting caspase-11 activation, interferon regulatory factor-1 induction, or signal transducer and activator of transcription-1 phosphorylation. Transfection of BV-2 cells with a p65 subunit of NF-kappaB abolished the apoptosis-attenuating effects of baicalein, indicating that the inhibition of NF-kappaB is a major mechanism of action. Baicalein, however, did not significantly affect NO donor-mediated cytotoxicity, and the apoptosis-attenuating effects of baicalein were independent of 12-lipoxygenase inhibition. Based on our previous findings that activation-induced cell death (AICD) of microglia occurs through two separate pathways (NO-dependent pathway and caspase-11-dependent pathway), our current results suggest that baicalein selectively inhibits the NO-dependent apoptotic pathway of activated microglia by suppressing cytotoxic NO production. Also, the AICD-inhibiting effects of baicalein were specific for the inflammatory stimulus that activated microglia.
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PMID:Flavonoid baicalein attenuates activation-induced cell death of brain microglia. 1260 97

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) regulate cell growth, protein synthesis, and apoptosis in response to nutrients and mitogens. As an important source of nitric oxide during inflammation, human inducible nitric oxide synthase also plays a role in the regulation of cytokine-driven cell proliferation and apoptosis. The role of mTOR and PI3K in the activation of human inducible nitric oxide synthase transcription by cytokines and lipopolysaccharide (LPS) was investigated in lung epithelial adenocarcinoma (A549) cells. LY294002, a dual mTOR and PI3K inhibitor, blocked human inducible nitric oxide synthase (hiNOS) promoter activation and mRNA induction by cytokines and LPS in a PI3K-independent fashion. On gene expression analysis, LY294002 selectively blocked the induction of a subset of 14 LPS/interferon-gamma (IFN-gamma)-induced genes, previously characterized as signal transducer and activator of transcription-1 (STAT1)-dependent. LY294002, but not wortmannin, inhibited LPS/IFN-gamma-dependent STAT1 phosphorylation at Ser-727 and STAT1 activity. Consistent with dual inhibition of mTOR and PI3K by LY294002, dominant-negative mTOR, anti-mTOR small interfering RNA, or rapamycin each inhibited phosphorylation of STAT1 only in the presence of wortmannin. LPS/IFN-gamma led to the formation of a macromolecular complex containing mTOR, STAT1, as well as protein kinase C delta, a known STAT1alpha kinase. Thus, LPS and IFN-gamma activate the PI3K and mTOR pathways, which converge to regulate STAT1-dependent transcription of pro-apoptotic and pro-inflammatory genes in a rapamycin-insensitive manner.
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PMID:Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin. 1280 16

Although interferon-gamma (IFN-gamma) induces the transporter associated with antigen processing (Tap)-1 expression in macrophages, cooperation with lipopolysaccharide signaling through Toll-like receptor 4 (TLR4) accelerates the kinetics and increases the overall levels of this gene. In this report, we show that peptidoglycan signaling through TLR2 and bacterial CpG DNA signaling through TLR9 are functionally equivalent at synergizing with IFN-gamma in regulating Tap-1 expression in macrophages. Activation of the p38 mitogen-activated protein kinase is necessary for this response, which correlates with increased phosphorylation of signal transducer and activator of transcription-1 on serine 727. Activation of p38, however, is not sufficient, as this signaling event does not affect the response to IFN-gamma in HeLa cells. The cooperation between these different signaling pathways also requires membrane fluidity. These data suggest that macrophages possess an ability to coordinate the signaling between the IFN-gamma and TLR receptors.
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PMID:p38 activation through Toll-like receptors modulates IFN-gamma-induced expression of the Tap-1 gene only in macrophages. 1469 83

Since macrophages (Mphis) are a first line of defense against pathogens, and are involved in both innate and adaptive immunity, understanding the impact of aging on Mphi function is important. In the past studies, we and others have shown that aging decreases Mphi responsiveness to classical activating signals (e.g. IFN-gamma and lipopolysaccharide, LPS). In this study, we examined the impact of aging on Mphi signaling through the IFN-gamma receptor pathway. Mphis from male Balb/c mice aged 2 (young) and 18-24 (old) months were purified and then stimulated with IFN-gamma. Western blotting revealed a significant reduction ( approximately 50%) in IFN-gamma-stimulated tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1) alpha and beta in Mphis from aged, when compared with young mice. This reduction in phospho-STAT-1 was associated with a significant constitutive reduction ( approximately 80%) in total STAT-1alpha protein and a complete inhibition of STAT-1 gene expression in response to IFN-gamma in old compared to young mice. These data may, in part, explain why classical Mphi responses like reactive nitrogen and oxygen species generation, tumor killing and microbicidal activity are lower in Mphis from aged subjects. We conclude that peritoneal Mphis from aged mice have an intrinsic defect in Jak-STAT signaling which prevents them from fully responding to IFN-gamma.
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PMID:Macrophage hypo-responsiveness to interferon-gamma in aged mice is associated with impaired signaling through Jak-STAT. 1503 19

Nitric oxide (NO) can be produced in large amounts by up-regulation of inducible NO synthase (iNOS). iNOS is induced in many cell types by pro-inflammatory agents, such as bacterial lipopolysaccharide (LPS) and cytokines. Overproduction by endothelial cells (EC) may contribute to vascular diseases. In contrast to macrophages, murine aortic endothelial cells (MAEC) produced no NO in response to either LPS or interferon gamma (IFNgamma), whereas combined treatment was highly synergistic. In this study, we investigated the mechanisms of synergy in MAEC. LPS activated p38 mitogen-activated protein kinase (MAPK), whereas IFNgamma activated Janus kinase and signal transducer and activator of transcription-1 (STAT1). Both pathways were required for iNOS induction because herbimycin A, a tyrosine kinase inhibitor, and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole. HCl (SB202190), a p38 MAPKalpha/beta inhibitor, each blocked induction. LPS increased the phosphorylation of STAT1alpha at serine 727 in IFNgamma-treated MAEC. SB202190, but not 2'-amino-3'-methoxyflavone (PD98059), an inhibitor of p44/p42 MAPK activation, abolished the phosphorylation and induction of iNOS. SB202190 did not affect tyrosine 701 phosphorylation or nuclear translocation of STAT1. However, STAT1-DNA binding activity was reduced by SB202190. Although LPS stimulated the DNA binding activity of nuclear factor kappaB and activating protein-1, combined treatment with IFNgamma did not enhance activation, and SB202190 did not inhibit it. The results indicate that p38 MAPKalpha and/or beta are required for the synergistic induction of iNOS by LPS and IFNgamma in MAEC. Furthermore, the synergistic induction is associated with phosphorylation of STAT1alpha serine 727 in MAEC. This observation may explain potentially beneficial effects of p38 MAPK inhibitors in vascular inflammatory diseases.
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PMID:p38 Mitogen-activated protein kinase mediates synergistic induction of inducible nitric-oxide synthase by lipopolysaccharide and interferon-gamma through signal transducer and activator of transcription 1 Ser727 phosphorylation in murine aortic endothelial cells. 1526 21


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