UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, mediates the toxicity associated with elemental, inorganic, and organic mercurial compounds. Studies of cellular events associated with Hg(2+) toxicity have focused largely on disruption of cell membranes and impairment of mitochondrial functions. In contrast, few studies have sought to define the specific molecular mechanisms through which Hg(2+) might affect toxicity via alteration of thiol-dependent signal transduction pathways that regulate cell proliferation and survival. Of particular interest in this regard is the effect of Hg(2+) on nuclear factor-kappaB (NF-kappaB), a pleiotropic transcriptional factor that is known to require reduced cysteine moieties at critical steps of activation and DNA binding. Here, we evaluated the effects of Hg(2+) on the expression of NF-kappaB in normal rat kidney epithelial (NRK52E) cells, a principal target of Hg(2+) toxicity. The lipopolysaccharide (LPS)-inducible form of NF-kappaB was readily detected in kidney cells and has been characterized as the p50p65 heterodimer. NF-kappaB-DNA binding was prevented in a dose-related manner by Hg(2+) (0-55 microM) in vitro when added to DNA binding reactions containing the nonthiol reducing agent Tris(2-carboxyethyl)phosphine hydrochloride (TCEP). Similarly, Hg(2+) at the same concentrations prevented DNA binding of a human recombinant wild-type p50p50 homodimer in binding reactions, and this effect was attenuated using a mutant form of the p50 protein containing a cys(62)-->ser(62) mutation. The inhibition of p50-DNA binding by Hg(2+) was reversible in a dose-related manner in vitro by competitive thiols DTT, GSH, and l-cysteine in binding reactions. In contrast, competitive thiols added to nuclear binding reactions were unable to reverse attenuation of LPS-mediated NF-kappaB-DNA binding affinity when cells were pretreated in vivo with Hg(2+) at concentrations as low as 2 microM prior to LPS administration. Immunoblot analyses indicted that Hg(2+) pretreatment of kidney cells substantially diminished, in a dose-related manner, the concentration of p65 translocated into the nucleus following LPS administration. Additionally, Hg(2+) pretreatment impaired both the phosphorylation and degradation of IkappaBalpha, suggesting a specific effect on NF-kappaB activation at the level of IkappaBalpha proteolysis. Finally, Hg(2+) at concentrations as low as 5 microM significantly diminished NF-kappaB-mediated transcriptional activity when administered to kidney cells transiently transfected with an NF-kappaB-driven luciferase reporter gene (pLuc-4xNF-kappaB) prior to LPS treatment. These findings demonstrate that Hg(2+), at low cellular concentrations, attenuates NF-kappaB activation at sites associated with IkappaBalpha phosphorylation and degradation, nuclear translocation of the p50p65 heterodimer, and association of p50-cys(62) with the DNA kappaB binding site. Attenuation of NF-kappaB activation by Hg(2+) through these mechanisms may underlie apoptotic or other cytotoxic responses that are known to be associated with low level Hg(2+) exposure in kidney epithelial cells.
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PMID:Mercuric ion attenuates nuclear factor-kappaB activation and DNA binding in normal rat kidney epithelial cells: implications for mercury-induced nephrotoxicity. 1143 39

Chemioxyexcitation [deltapO2/reactive oxygen species (ROS)] constitutes a potential signaling mechanism for regulating an inflammatory signal associated with oxidative stress. Exposure of fetal alveolar type II epithelial cells to an ascending deltaPO2 regimen with or without the hydroxyl radical (OH) or the superoxide radical anion (O2*-) induces a dose-dependent release of pro-inflammatory cytokines. Similarly, the Escherichia coli-derived lipopolysaccharide (LPS) upregulates cytokine biosynthesis in a dose- and time-dependent manner. Irreversible inhibition by L-buthionine-(S,R)-sulfoximine (BSO) of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), induces intracellular accumulation of ROS and augments chemioxyexcitation and LPS-mediated release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha). Analysis of the molecular mechanism implicated reveals an inhibitory kappaB (IkappaB-alpha)/nuclear factor kappaB (NF-kappaB)-independent pathway mediating the redox-dependent regulation of inflammatory cytokines. Although BSO stabilizes cytosolic IkappaB-alpha and downregulates its phosphorylation, thereby blockading NF-kappaB activation, it augments cytokine biosynthesis in a dose-dependent manner. These results indicate that glutathione depletion is associated with augmentation of an oxidative stress-mediated pro-inflammatory state in an ROS-dependent mechanism and that the IkappaB-alpha/NF-kappaB pathway is otherwise not necessarily indispensable for redox-mediated regulation of cytokines.
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PMID:Glutathione depletion is associated with augmenting a proinflammatory signal: evidence for an antioxidant/pro-oxidant mechanism regulating cytokines in the alveolar epithelium. 1156 56

Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity.
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PMID:Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response. 1171 Sep 94

Kupffer cells are involved in the pathogenesis of chemically mediated liver injury through release of biologically active mediators that promote the pathogenic process. The purpose of this study was to elucidate specific biochemical and molecular changes occurring in Kupffer cells throughout a time course of carbon tetrachloride (CCl(4))-mediated liver injury and fibrosis. Rats were administered 1 ml/kg of CCl(4) (10% v/v olive oil) twice weekly for up to 6 weeks. Plasma alanine aminotransferase values and hematoxylin-and-eosin- and trichrome-stained liver sections indicated minor liver damage at 2 weeks followed by increased damage and collagen deposition by 4 and 6 weeks. Additionally, mRNA levels in Kupffer cells isolated from CCl(4)-treated rats demonstrated significant increases in tumor necrosis factor alpha (TNF alpha); tumor growth factor beta; interleukin-6 (IL-6); interleukin 1 beta; cyclooxygenase 2; CD14, and I kappa B alpha transcripts after 2 and 4 weeks of treatment. However, the expression of these genes at 6 weeks was similar to that of controls. Increased gene expression of cytokines in Kupffer cells isolated from CCl(4)-treated rats was accompanied by increases in protein production of TNF alpha, IL-6, IL-1 beta, and interleukin 10 following lipopolysaccharide stimulation. Further, liver sections stained for ED2-positive cells demonstrated an increase in the number of resident macrophages at 2 and 4 weeks with a slight decrease in ED2-positive cells by week 6 but still significantly more than control. Analysis of reduced glutathione (GSH) and oxidized glutathione (GSSG) indicated that Kupffer cells from CCl(4)-treated animals exhibited a 50% decrease in GSH at 2 and 4 weeks, whereas no significant changes were observed for GSSG. In conclusion, these data implicate Kupffer cells as a critical mediator of the inflammatory and fibrogenic responses during CCl(4)-mediated liver damage and provide new insight into the temporal molecular and biochemical changes associated with the ability of these resident macrophages to modulate liver injury.
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PMID:Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. 1173 48

Nitric oxide (NO) has been proved to be a mediator of hypoxic injury in renal proximal tubules (PT), but its effect on iron-induced cytotoxicity has remained little known. In this study, we observed the relationship between NO production and lactate dehydrogenase (LDH) release in primary proximal tubular epithelia co-incubated with different doses of NTA-Fe and lipopolysaccharide (LPS) alone or in combination. NO production was monitored by NO2 concentration in supernatants based on the Griess reaction; while the semi-quantitative RT-PCR was applied to detect the inducible nitric oxide synthase (iNOS) mRNA level induced by NTA-Fe and LPS together. In addition, experimental groups were subjected to reactive oxygen species (ROS) scavengers to determine the impact of the interaction between NO and ROS on iron-mediated cytotoxicity. After a 12-h co-incubation, we found that NTA-Fe increased both LDH release and NO2(-) production in a dose-dependent manner (P < 0.001). The level of iNOS mRNA induced by LPS was enhanced by 500 microM NTA-Fe (P < 0.01), lower or higher concentrations had no effect. However, the supernatantNO2(-) level in the same group did not change significantly (P > 0.05) although tubular injury was aggravated (P < 0.001). The addition of L-arginine increased LDH release from 25.05 +/- 8.36% in the iron group to 38.67 +/- 7.67% in iron plus LPS group (P < 0.05); concomitantly, L-NAME mitigated iron toxicity in LPS-treated PT (P < 0.05). Hydroxyl scavengers provided complete protection against iron-mediated cytotoxicity (P < 0.001), but the decrease of NO2(-) production was only significant in the LPS-treated group. In contrast, SOD was partially effective in the LPS group (P < 0.05) whereas the NO2(-) level in the supernatant was inversely raised (P < 0.05). GSH had no effect on either iron toxicity or NO2(-) production. Thus, we conclude that NO can exacerbate the cytotoxicity caused by NTA-Fe in cultured proximal tubular epithelia, but NO is not the only factor. NTA-Fe could enhance the upregulation of iNOS transcription induced by LPS in a specific concentration range, and its regulation of NO production might also involve a post-transcription mechanism. The hydroxyl group is the major mediator in our model and the pro-oxidant role of NO is probably due to its ability to promote the Fenton reaction and form both ONOO(-) and *OH via its interaction with ROS.
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PMID:Effect of nitric oxide on iron-mediated cytotoxicity in primary cultured renal proximal tubules. 1174 4

The pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, contribute to the exacerbation of pathophysiological conditions in the lung. The regulation of cytokines involves the reduction-oxidation (redox)-sensitive nuclear factor-kappaB (NF-kappaB), the activation of which is mediated through an upstream kinase that regulates the phosphorylation and subsequent degradation of inhibitory-kappaB (IkappaB)-alpha, the major cytosolic inhibitor of NF-kappaB. It was hypothesized that lipopolysaccharide (LPS)-induced biosynthesis of TNF-alpha and IL-6 in vitro is tightly regulated by redox equilibrium. Furthermore, the likely involvement of the IkappaB-alpha/NF-kappaB signalling transduction pathway in mediating redox-dependent regulation of LPS-induced cytokine biosynthesis was revealed. Using alveolar epithelial cells, the role of L-buthionine-(S,R)-sulfoximine (BSO), a specific and irreversible inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in glutathione (GSH - an antioxidant thiol) biosynthesis, in regulating LPS-mediated TNF-alpha and IL-6 production and the IkappaB-alpha/NF-kappaB signalling pathway was investigated. Pre-treatment with BSO, prior to exposure to LPS augmented, in a dose-dependent manner, LPS-induced TNF-alpha and IL-6 biosynthesis, an effect associated with the induction of intracellular accumulation of reactive oxygen species (ROS). Interestingly, BSO blocked the phosphorylation of IkappaB-alpha, reduced its degradation, thereby allowing its cytosolic accumulation, and subsequently inhibited the activation of NF-kappaB. These results indicate that there are ROS and redox-mediated effects regulating pro-inflammatory cytokines, and that the IkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially involved in mediating redox-dependent regulation of cytokine signaling.
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PMID:L-Buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, augments LPS-mediated pro-inflammatory cytokine biosynthesis: evidence for the implication of an IkappaB-alpha/NF-kappaB insensitive pathway. 1178 Nov 88

We cloned the cDNA for mouse microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and expressed the recombinant enzyme in Escherichia coli. The membrane fraction containing recombinant mPGES-1 catalyzed the isomerization of PGH2 to PGE2 in the presence of GSH with K(m) values of 130 microM for PGH2 and 37 microM for GSH, a turnover number of 600 min(-1), and a k(cat)/K(m) ratio of 4.6 min(-1) microM(-1). Recombinant mPGES-1 was purified and used to generate a polyclonal antibody highly specific for mPGES-1. The antibody showed a single band on Western blotting of microsomal fractions from lipopolysaccharide-treated mouse peritoneal macrophages. Northern and Western blotting analyses revealed that mPGES-1 was induced together with cyclooxygenase-2 in mouse macrophages after treatment of the cells with lipopolysaccharide. Confocal immunofluorescence microscopy revealed that both mPGES-1 and cyclooxygenase-2 were colocalized in the lipopolysaccharide-treated macrophages. Taken together, these results demonstrate that mPGES-1 is an efficient downstream enzyme for the production of PGE2 in the activated macrophages treated by lipopolysaccharide.
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PMID:Biochemical characterization of mouse microsomal prostaglandin E synthase-1 and its colocalization with cyclooxygenase-2 in peritoneal macrophages. 1179 91

The pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, contribute to the exacerbation of pathophysiological conditions in the lung. The regulation of cytokine gene transcription involves the reduction-oxidation (redox)-sensitive nuclear factor-kappaB (NF-kappaB), the activation of which is mediated through an upstream kinase that regulates the phosphorylation and subsequent degradation of inhibitory-kappaB (IkappaB)-alpha, the major cytosolic inhibitor of NF-kappaB. It was hypothesised that the lipopolysaccharide (LPS)-induced biosynthesis of TNF-alpha in vitro is regulated by redox equilibrium. Furthermore, the likely involvement of the IkappaB-alpha/NF-kappaB signalling transduction pathway in regulating LPS-induced TNF-alpha biosynthesis was unravelled. In a model of alveolar epithelial cells, we investigated the role of L-buthionine-(S,R)-sulfoximine (BSO), a specific and irreversible inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in glutathione (GSH) biosynthesis, in regulating LPS-mediated TNF-alpha production and the IkappaB-alpha/NF-kappaB pathway. Pretreatment with BSO, prior to exposure to LPS augmented, in a dose-dependent manner, LPS-induced TNF-alpha biosynthesis. In addition, BSO blockaded the phosphorylation of IkappaB-alpha, reduced its degradation, thereby allowing its cytosolic accumulation, and subsequently inhibited the activation of NF-kappaB. These results indicate that there are oxidant-initiated and redox-mediated mechanisms regulating TNF-alpha biosynthesis and that the IkappaB-alpha/NF-kappaB signal transduction pathway is redox-sensitive but differentially involved in redox-dependent regulation of cytokine signalling in the alveolar epithelium.
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PMID:Redox regulation of TNF-alpha biosynthesis: augmentation by irreversible inhibition of gamma-glutamylcysteine synthetase and the involvement of an IkappaB-alpha/NF-kappaB-independent pathway in alveolar epithelial cells. 1181 49

We examined whether changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione of human monocytes regulate lipopolysaccharide (LPS)-induced IL-12 production and defined the molecular mechanism that underlies glutathione redox regulation. Monocytes exposed to glutathione reduced form ethyl ester (GSH-OEt) or maleic acid diethyl ester (DEM) increased or decreased the intracellular GSH/GSSG ratio, respectively. LPS-induced IL-12 production and p38 mitogen-activated protein (MAP) kinase activation were enhanced by GSH-OEt but suppressed by DEM. Selective p38 inhibitors showed that p38 promoted GSH-OEt-enhanced IL-12 production. Furthermore, IFN-gamma priming increased the GSH/GSSG ratio and enhanced IL-12 production through p38, and DEM negated the priming effect of IFN-gamma on p38 activation and IL-12 production as well as on the GSH/GSSG ratio. These findings reveal that glutathione redox regulates LPS-induced IL-12 production from monocytes through p38 MAP kinase activation and that the priming effect of IFN-gamma on IL-12 production is partly a result of the glutathione redox balance.
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PMID:Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in IFN-gamma priming of IL-12 production. 1181 56

Redox regulation of mitogen-activated protein kinase (MAPK(p38))-mediated pro-inflammatory cytokine production is not well characterized in the alveolar epithelium. It was hypothesized that the involvement of the MAPK(p38) pathway in regulating lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha and interleukin-6 secretion is redox-sensitive and affected by NAC, an antioxidant and a precursor of glutathione, and L-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis. Exposure of fetal alveolar type II epithelial cells to Escherichia coli-derived LPS induced, in a time-dependent manner, the phosphorylation/activation of MAPK(p38) (peak at 15min). In addition, LPS up-regulated the phosphorylation of MAPK(p38) in a dose-dependent manner. The effect of LPS on the MAPK(p38) pathway was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small 27kDa heat-shock protein (Hsp27). LPS induced the phosphorylation of Hsp27 in a time- and dose-dependent manner. Selective blockage of the MAPK(p38) pathway by a pyridinyl-imidazole (SB-203580) abrogated LPS-induced release of TNF-alpha and IL-6. Pre-treatment with NAC reduced LPS-mediated secretion of TNF-alpha and IL-6. Incubation of cells with NAC induced intracellular accumulation of GSH, but reduced the concentration of GSSG. On the other hand, pre-treatment with BSO augmented LPS-mediated secretion of TNF-alpha and IL-6. In addition, BSO induced intracellular accumulation of GSSG, but reduced the concentration of GSH. Whereas NAC blocked the phosphorylation/activation of MAPK(p38), BSO amplified the LPS-mediated effect on MAPK(p38). These results indicated that intracellular redox signaling plays an important role in regulating LPS-induced activation of the MAPK(p38) pathway and MAPK(p38)-mediated regulation of LPS-dependent inflammatory cytokine production in the alveolar epithelium.
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PMID:The involvement of L-gamma-glutamyl-L-cysteinyl-glycine (glutathione/GSH) in the mechanism of redox signaling mediating MAPK(p38)-dependent regulation of pro-inflammatory cytokine production. 1184 6

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