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)

Resident peritoneal macrophages synthesized and released eicosanoids when challenged by zymosan, a phagocytosable particle. Incubation of these cells with ethanol resulted in dose-dependent inhibition of arachidonic acid release and eicosanoid generation in response to zymosan. Ethanol affected the extent but not the ratio of eicosanoids released. When assayed in a cell-free system, endogenous phospholipase A2 activity was neither affected by the presence of ethanol in the incubation medium nor by preincubation of the cells with ethanol. Ethanol also inhibited arachidonic acid release in response to phorbol myristate acetate, a compound that, like zymosan, triggered a pertussis-toxin-sensitive response. When cells that had been previously treated with pertussis toxin were used, no further inhibitory effect of ethanol was seen in response to both zymosan and phorbol myristate acetate. On the other hand, ethanol had no effect on arachidonic acid release stimulated by ionophore A23187 or lipopolysaccharide, two compounds that triggered a pertussis-toxin-insensitive response. Moreover, ethanol was able to nearly abolish arachidonic acid release in response to fluoroaluminate, a direct activator of G-proteins. Altogether, the results of this study suggest that ethanol inhibits zymosan-stimulated eicosanoid production by interacting with a G-protein--or a G-protein-mediated process--that is critically involved in arachidonic acid mobilization.
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PMID:Ethanol inhibits zymosan-stimulated eicosanoid production in mouse peritoneal macrophages. 828 Jul 70

This study examines the effects of chronic alcohol consumption on thymic apoptosis with or without pretreatment with E. coli lipopolysaccharide (LPS). Apoptotic cell death of thymocytes was monitored by DNA fragments in gel electrophoresis and the appearance of apoptotic cells by flow cytometry. Changes in mitochondrial membrane potential (MMP), as indicated by 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] uptake, and hydrogen peroxide (H2O2) production as indicated by oxidation of 2',7'-dichlorofluresin diacetate (DCFH-DA), were used to assess altered mitochondrial function. Glutathione levels were also determined to obtain information concerning alterations in the antioxidant potential in the cells. Male Sprague-Dawley rats, fed a nutritionally adequate liquid diet for 8-9 weeks, were divided in four groups: 1) saline-injected, diet controls; 2) LPS-injected, diet controls; 3) saline-injected, alcohol-consuming; and 4) LPS-injected, alcohol-consuming animals. LPS (0.5 mg/kg in 4 ml saline) or saline (4 ml) was continuously infused i.v. for 12 h before the experiments. The results showed that the weight and cell numbers of thymus from the chronic alcoholic rats were significantly less than values found in diet controls. Administration of LPS aggravated thymic apoptosis, as indicated by the presence of significant DNA fragments in gel electrophoresis and increased rate of apoptotic cells in flow cytometry. The alcohol-induced apoptotic changes were also accompanied by decreased MMP, indicating impaired mitochondrial function. Although H2O2 production by the total thymocyte population did not show marked changes among the experimental groups, the subpopulation of thymocytes exhibiting low H2O2 production was increased markedly in the LPS-treated groups. Ethanol consumption or LPS treatment decreased total glutathione concentration in the thymocytes. In summary, 1) chronic administration of alcohol induces atrophy of the thymus gland; 2) apoptosis is a major factor in thymic atrophy under these conditions; 3) chronic alcohol consumption is accompanied by alterations in mitochondrial function of the thymocytes, as indicated by decreased MMP and an increase in the low H2O2-producing cell subpopulation; 4) chronic alcohol abuse may impair intracellular defense mechanisms as reflected by the depletion of the intracellular antioxidant, glutathione; and 5) administration of LPS further enhances thymic apoptosis in chronic alcohol-consuming rats, suggesting that the dual insults of infection and chronic alcoholism exaggerate in vivo immunosuppression.
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PMID:Alcohol-induced thymocyte apoptosis is accompanied by impaired mitochondrial function. 901 30

Exposure to lipopolysaccharide (LPS) combined with phorbol-12-myristate-13-acetate (PMA) stimulates de novo synthesis of inducible nitric oxide synthase (NOS-2) in C6 glioma cells. Ethanol dose-dependently inhibits C6 cell NOS-2 activity, as measured by nitrite accumulation in culture medium, when present during LPS plus PMA treatment. The present study reports on mechanisms related to this inhibition. Ethanol added directly to cytosolic extracts did not inhibit NOS-2 catalytic activity, nor did ethanol decrease nitrite accumulation when added to cultures 24 hr after LPS plus PMA treatment. In contrast, NOS-2 enzymatic activity was significantly decreased in cytosolic extracts from cultures simultaneously exposed to ethanol and LPS plus PMA for 24 hr. Immunoblot analysis showed a coincident decrease in NOS-2 protein immunoreactivity. RNA analysis revealed that NOS-2 mRNA was decreased at both 12 and 24 hr during LPS plus PMA induction in the presence of ethanol. Subsequent experiments confirmed that 12-hr exposure to ethanol was sufficient to inhibit LPS/PMA-induced NOS-2 activity. Ethanol exposure also inhibited NOS-2 activity induced by LPS plus interferon-gamma, by LPS plus tumor necrosis factor-alpha and by tumor necrosis factor-alpha alone. These data point to an inhibitory ethanol effect at a site downstream from cytokine receptor activation and second messenger signal transduction mechanisms leading to suppression of NOS-2 gene expression in C6 cells.
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PMID:Suppression by ethanol of inducible nitric oxide synthase expression in C6 glioma cells. 910 44

Inducible nitric oxide synthase (iNOS) mRNA is up-regulated in vivo by dibutyryl-cAMP (db-cAMP), the purine-2y receptor agonist 2-methylthio-ATP and Escherichia coli endotoxin lipopolysaccharide (LPS). Ethanol and diethyldithiocarbamate inhibit LPS-stimulated iNOS mRNA. Their effects on db-cAMP- and 2-methylthio-ATP-stimulated iNOS mRNA remain undefined. We examined the effect of ethanol (4.5 g/kg intraperitoneal) and intratracheal diethyldithiocarbamate (5 mg/kg) on intratracheal LPS (0.6 mg/kg), db-cAMP (0.1 and 1 mg/kg) or 2-methylthio-ATP (5 mg/kg)-stimulated rat alveolar macrophage (AM) iNOS mRNA and protein, reactive nitrogen intermediates nitrite and nitrate anion (RNI) and nuclear transcription factor-kappaB (NF-kappaB) in vivo. LPS and the autacoids increased iNOS mRNA and protein in rat AM and RNI in bronchoalveolar lavage fluid and in ex vivo incubates of AM compared with these parameters in control rats (n = 6-21/group). Only LPS up-regulated TNF-alpha mRNA and release of TNF-alpha in bronchoalveolar lavage fluid and AM. Ethanol inhibited LPS stimulation of the iNOS cascade at the level of transcription but inhibited only autacoid-stimulated iNOS protein and RNI. Diethyldithiocarbamate selectively inhibited the LPS-stimulated iNOS cascade at the level of transcription. Coadministration of ethanol and diethyldithiocarbamate inhibited LPS-stimulated iNOS mRNA, protein and RNI more than either inhibitor alone but did not differ from ethanol alone on autacoid-stimulated iNOS protein or RNI. LPS increased and db-cAMP did not affect NF-kappaB in AM. Ethanol inhibited LPS-stimulated NF-kappaB. Thus, two distinct pathways exist for induction of iNOS mRNA in rat AM in vivo: an NF-kappaB pathway for LPS and cytokines inhibitable by ethanol and diethyldithiocarbamate and an NF-kappaB-independent pathway, refractory to inhibition by ethanol and diethyldithiocarbamate for db-cAMP and 2-mes-ATP. Finally, ethanol inhibits iNOS at the level of transcription and at the level of the enzyme.
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PMID:Interaction of ethanol with inducible nitric oxide synthase messenger RNA and protein: direct effects on autacoids and endotoxin in vivo. 926 74

Ethanol consumption results in significant changes in the immune system of experimental animals and humans. Previous work by ourselves and others has established that in utero exposure to ethanol results in alterations in the immune system of the offspring that persist into adult life. The present study was designed to determine if prenatal exposure to ethanol results in increased vulnerability to the immunosuppressive effects of ethanol consumption in adulthood. Male and female Sprague-Dawley offspring were selected in adulthood from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) groups, and given either an ethanol-containing liquid diet or were pair-fed an isocaloric liquid diet without ethanol for 30 days. At the end of the 30-day feeding period, lymphocyte responses to the mitogens concanavalin A (Con A) and lipopolysaccharide, and to interleukin-2 (IL-2) were tested using in vitro assays. The results of this study support and extend previous data demonstrating long-term adverse effects of prenatal ethanol exposure on T-cell responses to mitogens, and provide further evidence that deficits seem to be more robust in male than in female offspring. Prenatal E males showed reduced T-lymphocyte proliferation to Con A and T-lymphoblast proliferation to IL-2, compared with their prenatal PF and C counterparts, regardless of whether they were exposed to the ethanol or the control diet in adulthood. In addition, T-lymphoblast proliferation to IL-2 was suppressed in prenatal E, compared with prenatal C, females exposed to control diet in adulthood. This is the first report of a deficit in T-cell aspects of immunity in E females, although it appears that this deficit may have been partially mediated by nutritional effects. A second major finding in this study is that consumption of ethanol diet in adulthood in itself had significant immunosuppressive effects on T-cell responses in both males and females. However, contrary to our expectation, previous exposure to ethanol in utero did not exacerbate the changes in immune responsiveness that were observed after adult ethanol consumption.
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PMID:Influence of ethanol consumption on immune competence of adult animals exposed to ethanol in utero. 958 45

The production of interleukin-8 (CINC: cytokine-induced neutrophil chemo-attractant) from different cell populations in the rat liver was studied and cells related to the initiation of CINC production in lipopolysaccharide (LPS)-injected endotoxaemic rats were characterized. Sinusoidal endothelial cells (16.4 +/- 10.6 ng/mL) produced significantly higher amounts of CINC in 24 h primary cultures compared with hepatocytes (0.9 +/- 0.9 ng/mL; P < 0.05) and Kupffer cells (6.5 +/- 5.1 ng/mL; P < 0.05). Lipopolysaccharide, tumour necrosis factor-alpha (TNF-alpha), and interleukin-1 alpha (IL-1 alpha) stimulated different liver cell populations to produce CINC; LPS mainly stimulated Kupffer cells. TNF-alpha stimulated hepatocytes and IL-1 alpha stimulated all three types of cells. Intraperitoneal injection of LPS (4 mg/kg) caused CINC accumulation in non-parenchymal cells of the rat liver within 1 h of injection, as shown by immunohistochemical staining. In contrast, CINC-positive hepatocytes were not seen until 3 h after injection of LPS. Ethanol was not a direct inducer of CINC production by rat hepatocytes in vitro. These findings strongly suggest that non-parenchymal liver cells, including sinusoidal endothelial cells, are the main source of CINC. Our data also suggest that during endotoxaemia, CINC production is initiated by non-parenchymal cells and this is followed by production from hepatocytes.
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PMID:Induction of CINC (interleukin-8) production in rat liver by non-parenchymal cells. 971 20

Ethanol (ETOH) selectively suppressed Escherichia coli endotoxin lipopolysaccharide (LPS)-stimulated, but not dibutyryl cAMP (db-cAMP)-stimulated upregulation of inducible nitric oxide synthase (iNOS) in rat alveolar macrophages (AMs) in vivo (Zhao et al., Alcohol. Clin. Exp. Res. 21:1062-1074, 1997). LPS-induced stimulation of iNOS is inhibited in vitro by db-cAMP and purine-2-Y (P2Y) receptor-mediated agonists. We examined the effect of ETOH on this interaction in rat lung AMs in vivo. Two hours after co-administration of LPS [0.6 mg/kg, intratracheal (i.t.)] with db-cAMP (0.1 mg/kg, i.t.) or 2-methylthio-adenosine-triphosphate (2-mes-ATP) to Sprague-Dawley rats (225 to 250 g) (n = 10 to 24/gp) iNOS messenger ribonucleic acid (mRNA), iNOS protein, and nitrate and nitrite anions [reactive nitrogen intermediates (RNIs)] in bronchoalveolar lavage fluid (BALf), and the ex vivo incubates of AMs were increased more than when these compounds were given individually to the rats. Co-administration of LPS with the autacoids did not affect LPS-stimulated increases of tumor necrosis factor-alpha (TNF alpha) mRNA, but inhibited LPS-stimulated BALf TNF alpha protein and attenuated LPS-mediated decreases of cell-associated TNF alpha. Pretreatment of rats with ETOH (4.5 g/kg, i.p.) or diethyidithiocarbamate (DETC; 5 mg/kg, i.t.), an inhibitor of the nuclear transcription factor NF kappa B (NF-kappaB), 30 min before co-administration of LPS with the autacoids restored iNOS mRNA levels to that obtained with the autacoid alone. Pretreatment of rats with ETOH decreased iNOS protein and RNI below that produced by either compound given individually to the rats. Although pretreatment of rats with DETC also decreased iNOS protein and RNI levels produced by LPS, the levels of both substances were elevated above that of the autacoid alone, LPS-induced upregulation of iNOS mRNA was associated with elevated levels of p65/p50 NF-kappaB in the nucleus of AMs. Neither db-cAMP or 2-mes-ATP affected LPS-stimulated NF-kappaB-DNA binding. Moreover, ETOH and DETC inhibited LPS-stimulated NF-kappaB-DNA binding. We conclude that in rat AMs in vivo: (1) both db-cAMP and P2Y-receptor stimulation summate with, rather than inhibit, LPS-induced upregulation of the iNOS mRNA, protein, and RNI; (2) ETOH and DETC inhibit LPS-induced upregulation of iNOS mRNA only when stimulated through the NF-kappaB pathway; and (3) ETOH inhibits both autacoid and LPS-stimulated formation of iNOS protein by a mechanism independent of its ability to suppress iNOS transcription.
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PMID:Ethanol inhibits the potentiation of endotoxin by dibutyryl cAMP and 2-methylthio ATP in vivo. 983 79

Alcohol's suppressive effects on polymorphonuclear leukocyte (PMN) production and function increases host susceptibility to a wide variety of infections and impairs the ability of these effector cells to seek and destroy invading pathogens. Granulocyte colony-stimulating factor (G-CSF), an important regulator of PMN production and function, is known to be increased in the plasma during infectious episodes. In previous studies we found acute alcohol intoxication to suppress the tumor necrosis factor-alpha (TNF alpha) response to in vivo challenges with bacteria or lipopolysaccharide. The present study was initiated to determine the impact of alcohol intoxication on the plasma G-CSF response to gram-negative infection. For this purpose, rats received an intravenous challenge of Escherichia coli (10(6) CFU) 30 min after an intraperitoneal injection of ethanol (5.5 g/kg) or an equivalent volume of saline (control). Ethanol-intoxicated rats had a greater 48 hr mortality to live E. coli injection than did unintoxicated animals (45% vs. 8%). Despite an increased bacterial burden in both the lung and liver at 24 hr after initiating E. coli infection in alcohol-intoxicated animals, PMN tissue recruitment, indexed as myeloperoxidase activity, did not differ between control and alcohol-treated rats. Moreover, alcohol suppressed blood PMN phagocytic capacity to a greater extent in animals given alcohol than controls at 5 and 24 hr after initiating infection. In control animals after intravenous E. coli injection, bioactive G-CSF increased in plasma and peaked near 300 ng/ml at 8 hr. In rats pretreated with alcohol, the plasma G-CSF response was markedly suppressed in response to intravenous E. coli (p < 0.05). In a second experiment, neutralization of the E. coli-induced plasma TNF alpha response by pretreatment with anti-TNF alpha antibody similarly inhibited the plasma G-CSF response. These results support the postulate that alcohol-induced inhibition of TNF alpha directly contributes to the adverse effects of alcohol on PMN function by suppressing the normal autocrine amplification pathway responsible for G-CSF production.
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PMID:Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication. 983 89

Ethanol impairs hormone-stimulated cAMP production in a number of cell types, yet the effects of ethanol on downstream responses mediated by cAMP-dependent protein kinase (PKA) are not understood. Here we have investigated the effects of ethanol feeding on cAMP-mediated inhibition of tumor necrosis factor-alpha (TNF-alpha) synthesis in rat Kupffer cells. Male Wistar rats were fed liquid diets containing 36% of calories as ethanol for 4 wk or were pair fed a control diet. Stimulation of cAMP production by the adenosine A2 receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA), prostaglandin E2, or forskolin was decreased to 25% of control values in Kupffer cells isolated from ethanol-fed rats. This decrease was associated with a reduction in the quantity of immunoreactive Gsalpha protein in ethanol-fed rats, with no changes observed in Gialpha or Gbeta. TNF-alpha production was higher in ethanol-fed rats in response to stimulation with lipopolysaccharide or latex beads. Despite the profound reduction in the ability of hormone to increase cAMP production, NECA and prostaglandin E2 inhibited TNF-alpha production to an equivalent degree in Kupffer cells from ethanol- and pair-fed rats. Total activity and immuoreactive protein quantity of PKA did not differ between groups. Activation of PKA in response to a 15-min treatment with 1 microM NECA was reduced by 50% in ethanol-fed rats compared with control. Despite this reduction in activation, translocation of the catalytic subunit of PKA to the nucleus and phosphorylation of cAMP response element binding protein in response to activation were observed in Kupffer cells from both ethanol- and pair-fed rats. These data demonstrate that there is a dissociation between ethanol-induced desensitization of hormone-stimulated cAMP production in rat Kupffer cells and the downstream inhibition of TNF-alpha production mediated by cAMP.
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PMID:Ethanol dissociates hormone-stimulated cAMP production from inhibition of TNF-alpha production in rat Kupffer cells. 988 84

1. Ethanol inhibits inducible nitric oxide synthase (iNOS) expression in C6 glioma cells by an unknown mechanism. Because relatively high concentrations are needed for inhibition in drug-naive cells (IC50 approximately = to 150 mM), suppression due to cytotoxicity is one possible mechanism that has not been ruled out. Therefore, the present study examined the effects of ethanol and other alkanols on C6 glioma cell viability and iNOS activity to better understand the mechanism for inhibition. 2. iNOS expression was induced in cell culture with lipopolysaccharide and phorbol ester treatment. Nitrite accumulation in culture medium, the in vitro conversion of [3H]-L-arginine to [3H]-L-citrulline, and immunoblotting were used to quantify iNOS induction and activity. Trypan blue exclusion, extracellular release of lactate dehydrogenase, and quantity of total cell protein were used as measures of viability. 3. Short chain alkanols, methanol through 1-heptanol, concentration-dependently inhibited nitrite accumulation. Longer chain alkanols, 1-octanol and 1-decanol, did not except at cytotoxic concentrations. Experiments indicated short chain alkanol inhibition was not due to direct actions on iNOS catalytic activity, but that it transpires during iNOS induction. Immunoblots showed reduced iNOS protein levels. 4. Correlation analysis ruled out iNOS inhibition as being due to decreased cell number, total cell protein, or cell viability. In contrast, there was significant correlation with physical measures of lipophilicity. 5. In conclusion, inhibition of iNOS expression by ethanol and other short chain alkanols is not due to cytotoxicity. Instead, the strong correlation with lipophilicity suggests the inhibition derives from an interaction with unknown hydrophobic cellular sites.
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PMID:Effects of short chain alkanols on the inducible nitric oxide synthase in a glial cell line. 1020 16


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