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)

Uptake of oxidized low-density lipoprotein (LDL) by monocyte/macrophages to form "foam" cells has been implicated in atherogenesis. Activated monocyte/macrophages synthesize nitric oxide (NO) from L-arginine. NO is cytotoxic, antiproliferative, and a vasodilator that inhibits platelet and monocyte adhesion. NO synthase mRNA, protein, and enzyme activity were induced in J774.A1 macrophages activated with lipopolysaccharide and gamma interferon. When macrophages were incubated with oxidized LDL for 24 hours and activated, there was a dose- and time-dependent inhibition of NO synthesis, assessed as nitrite accumulation in the media. When activated cells were incubated with nontoxic doses of lipoprotein (25 micrograms/mL), neither native LDL nor acetyl LDL inhibited NO production, whereas oxidized LDL produced 50% inhibition. Levels of enzyme protein were unchanged by Western blot. Inhibition was a function of the degree of oxidation of LDL but was independent of cholesteryl esterification by the cells. Incubations of oxidized LDL with cells that had been pretreated with dextran sulfate or cytochalasin B yielded no evidence that inhibition was dependent on the scavenger receptor or directed endocytosis. Kinetic studies of inducible NO synthase from J774.A1 cells that were incubated with increasing doses of oxidized LDL indicated a pattern of noncompetitive inhibition. Inhibition of the enzyme was produced by lipids extracted from oxidized LDL but not by lipids extracted from native LDL. Because phosphatidylcholine (PC) is converted to lysophosphatidylcholine (LPC) during the oxidation of LDL, the effects of LPC were investigated. PC vesicles containing LPC did not inhibit enzyme activity but produced modest reductions in nitrite accumulation from cells. In contrast, PC vesicles had no significant effect. The data indicate that oxidized LDL lipid inhibits the activity of inducible NO synthase in activated macrophages. NO production by this enzyme and its inhibition by oxidized LDL lipid may influence cell-to-cell interactions and vasomotor tone in atherosclerotic blood vessels.
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PMID:Inhibition of inducible nitric oxide synthase in macrophages by oxidized low-density lipoproteins. 750 15

Rat brain glial cells have the capacity to express a calcium-independent form of nitric oxide synthase (iNOS). To test if iNOS induction required tyrosine kinase activity, we made use of genistein, a selective inhibitor of tyrosine kinases. In both primary astrocyte cultures and C6 glioma cells, the presence of genistein prevented both lipopolysaccharide- and cytokine-induced NOS activity in a dose-dependent manner. The presence of tyrphostin-25 (10 microM), which is highly specific for tyrosine kinases, also blocked iNOS induction. Additional characterization showed that genistein blocked iNOS induction in a dose-dependent manner (IC50 of approximately 40 microM), that the continuous presence of genistein was not necessary to observe inhibition, and that preincubation with genistein led to higher levels of inhibition than the simultaneous addition of genistein and inducers. The decrease in iNOS activity due to genistein was accompanied by a decrease in iNOS mRNA level as detected by a specific PCR assay. These results indicate that induction of astroglial iNOS expression requires tyrosine kinase activity.
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PMID:Nitric oxide synthase expression in glial cells: suppression by tyrosine kinase inhibitors. 750 17

1. The effect of endotoxin (E. coli lipopolysaccharide) on the induction of nitric oxide synthase (NOS) and the changes in vascular permeability in the colon and jejunum over a 5 h period have been investigated in the rat. 2. Under resting conditions, a calcium-dependent constitutive NOS, determined by the conversion of radiolabelled L-arginine to citrulline, was detected in homogenates of both colonic and jejunal tissue. 3. Administration of endotoxin (3 mg kg-1, i.v.) led, after a 2 h lag period, to the appearance of calcium-independent NOS activity in the colon and jejunum ex vivo, characteristic of the inducible NOS enzyme. 4. Administration of endotoxin led to an increase in colonic and jejunal vascular permeability after a lag period of 3 h, determined by the leakage of radiolabelled albumin. 5. Pretreatment with dexamethasone (1 mg kg-1 s.c., 2 h prior to challenge) inhibited both the induction of NOS and the vascular leakage induced by endotoxin. 6. Administration of the NO synthase inhibitor NG-monomethyl-L-arginine (12.5-50 mg kg-1, s.c.) 3 h after endotoxin injection, dose-dependently reduced the subsequent increase in vascular permeability in jejunum and colon, an effect reversed by L-arginine (300 mg kg-1, s.c.). 7. These findings suggest that induction of NOS is associated with the vascular injury induced by endotoxin in the rat colon and jejunum.
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PMID:The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat. 750 78

Nitric oxide (NO) contributes to the antitumor, antimicrobial, and immunosuppressive activity of macrophages. An inducible form of NO synthase (iNOS) is responsible for high output generation of nitric oxide by macrophages after stimulation with cytokines and/or lipopolysaccharide (LPS). In the present study, we demonstrate that interleukin 4 (IL-4) suppressed production of NO by primary mouse peritoneal macrophages exposed to IFN-gamma with or without LPS, even while synergizing with IFN-gamma to increase the secretion of TNF-alpha. Suppression of NO production was paralleled by decreases in iNOS enzyme activity and iNOS antigen. IL-4 did not inhibit induction of iNOS mRNA 4-6 h after exposure to IFN-gamma, but strongly reduced iNOS mRNA at later times of stimulation (24-72 h), without increasing its turnover. The conditions for maximal suppression of iNOS expression by IL-4 and the mechanisms of suppression differed from those determined in parallel for transforming growth-factor-beta as described elsewhere. These results illustrate the diversity of phenotypes of macrophages deactivated by different cytokines, and demonstrate that IL-4 has the potential to reduce one component of the anti-tumor, antimicrobial, and immunosuppressive activities of macrophages.
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PMID:Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages. 750 68

1. Effects of dexamethasone on induction of nitric oxide (NO) synthase and L-arginine transport by lipopolysaccharide (LPS) were examined in a murine cultured macrophage cell line J774. Metabolism of L-arginine to L-citrulline and subsequent changes in intracellular amino acids pools were correlated with changes in nitrite production. 2. Despite a high intracellular concentration of arginine in activated J774 cells, LPS (1 microgram ml-1, 8 h) induced a 2.4 fold increase in arginine transport. Treatment of cells with cycloheximide (1 microgram ml-1) inhibited the time-dependent (1-8 h) induction of NO synthase and arginine transport mediated by LPS. 3. Induction of NO synthase by LPS (1 microgram ml-1, 24 h) alone was accompanied by a marked increase in arginine utilisation leading to decreased intracellular arginine levels and elevated intracellular and extracellular L-citrulline levels. These changes were further enhanced in the presence of interferon-gamma (IFN-gamma, 100 units ml-1, 24 h). 4. Dexamethasone (1 microM) abolished the increases in both nitrite and citrulline production induced by LPS alone but only partially reversed the combined effects of LPS and IFN-gamma. In contrast, treatment of cells with dexamethasone (10 microM) had no effect on the LPS-mediated induction of arginine transport or the decrease in intracellular arginine concentration. 5. We conclude that induction of arginine transporter activity in LPS-stimulated J774 cells involves de novo synthesis of carrier proteins, which increases transport of exogenous arginine during enhanced NO production. Moreover, the intracellular signalling pathways mediating induction of arginine transport and of NO synthase by LPS in activated macrophages diverge, since only the latter is sensitive to dexamethasone.
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PMID:Selective inhibition by dexamethasone of induction of NO synthase, but not of induction of L-arginine transport, in activated murine macrophage J774 cells. 750 26

The purpose of these studies was to determine whether the induction of NO synthase activity in murine K-1735 melanoma cells correlated with their metastatic potential. Nonmetastatic, metastatic, and somatic cell hybrids (produced by fusion of nonmetastatic and metastatic cells) were injected i.v. into syngeneic C3H/HeN mice. Metastatic cells survived to produce experimental lung metastases, whereas nonmetastatic cells did not. The various clones and somatic cell hybrids were incubated in vitro with combinations of tumor necrosis factor, interleukin 1, gamma-interferon, and lipopolysaccharide. Nonmetastatic cells exhibited high levels of inducible NO synthase activity and NO, whereas metastatic cells did not. Both the cytotoxic effects of the cytokines and NO production were inhibited by the addition of NG-monomethyl-L-arginine, a specific inhibitor of NO synthase. These data demonstrate an inverse correlation between production of endogenous NO and the ability of K-1735 cells to survive in syngeneic mice to produce lung metastases.
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PMID:Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. 750 36

The expression of mRNA for the inducible form of nitric oxide synthase, (iNOS), was studied in rat aortic smooth muscle cells, (SMCs) in cell culture and in strips of rat aorta by reverse transcriptase coupled to the polymerase chain reaction. iNOS mRNA expression was weak in cultured SMCs when exposed to either interferon-gamma (IFN gamma) or lipopolysaccharide (LPS), but the combination LPS+IFN gamma enhanced the expression. In aortic strips LPS alone induced a pronounced expression, with no further increase by IFN gamma. Cycloheximide potentiated the expression of iNOS mRNA in SMCs in culture stimulated with LPS+IFN gamma but attenuated the response in aortic strips. The results indicate different cellular signaling pathways for the induction of iNOS mRNA by LPS and/or IFN gamma, in cultured SMCs and in rat aortic strips.
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PMID:Different induction mechanisms of mRNA for inducible nitric oxide synthase in rat smooth muscle cells in culture and in aortic strips. 750 6

Regulation of nitric oxide synthase mRNA by interferon-gamma, tumor necrosis factor-alpha, bacterial lipopolysaccharide (LPS) and dexamethasone in rat aortic endothelial cells was examined. The combination of interferon-gamma (100 U/ml) and tumor necrosis factor-alpha (5000 U/ml) evoked a time-dependent increase in nitric oxide synthase mRNA and nitrite/nitrate production, both of which were inhibited by dexamethasone. Neither interferon-gamma (100 U/ml), tumor necrosis factor-alpha (5000 U/ml) nor LPS (100 ng/ml) alone was capable of increasing nitric oxide synthase mRNA and nitrite/nitrate production in these cells. However, combinations of two of the three agents synergistically increased both nitric oxide synthase mRNA and nitrite/nitrate production. When the three agents were applied simultaneously, nitric oxide synthase mRNA and nitrite/nitrate production were both markedly increased. LPS contamination, which may affect the induction of nitric oxide synthase, was below 20 pg/ml in all experiments unless LPS was added exogenously, namely, the effects observed were those of the cytokines themselves. Our results suggest that in endothelial cells, these cytokines regulate the production of nitric oxide at the level of nitric oxide synthase mRNA induction.
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PMID:Nitric oxide synthase mRNA in endothelial cells: synergistic induction by interferon-gamma, tumor necrosis factor-alpha and lipopolysaccharide and inhibition by dexamethasone. 750 9

The effects of interleukin-1 alpha, tumor necrosis factor-alpha and dexamethasone on the induction of nitric oxide synthase mRNA in rat aortic smooth muscle cells were studied. Neither interleukin-1 alpha (up to 100 U/ml) nor tumor necrosis factor-alpha (up to 5000 U/ml) was capable of inducing nitrite/nitrate production and nitric oxide synthase mRNA in smooth muscle cells. In contrast, treatment for 12 hr or longer with a combination of the two synergistically induced nitrite/nitrate and cyclic GMP production in cell culture media and nitric oxide synthase mRNA, both of which were prevented by dexamethasone. Contamination with bacterial lipopolysaccharide, which may affect the induction of nitric oxide synthase, was below 30 pg/ml in all experiments. Our findings show that dexamethasone and these cytokines regulate the induction of nitric oxide synthase at the mRNA level in vascular smooth muscle cells.
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PMID:Dexamethasone inhibits nitric oxide synthase mRNA induction by interleukin-1 alpha and tumor necrosis factor-alpha in vascular smooth muscle cells. 750 10

Bacterial lipopolysaccharide (LPS) has been recognized as one of the most potent activating signals for mouse peritoneal macrophages. In macrophages primed by interferon-gamma (IFN-gamma) or trehalose dimycolate (TDM), LPS induces NO synthase and the events associated with a high nitric oxide output: antitumor and antiparasitic activities. In the present report, it is shown that drugs (calcium ionophores or thapsigargin) which elevate the concentration of cytosolic calcium, [Ca2+]i, induce NO synthase and antitumor activities in primed macrophages, mimicking LPS action. Calcium ionophores and thapsigargin trigger NO synthase activity in macrophages primed in vivo by TDM, in thioglycollate-elicited macrophages primed in vitro by IFN-gamma, and in IFN-gamma-treated EMT6 adenocarcinoma cells. However, activation of TDM-primed macrophages by LPS does not seem to involve calcium fluxes: (i) no change in [Ca2+]i was detectable in TDM-primed macrophages loaded with Fura-2 and exposed to LPS, and (ii) activation of TDM-primed macrophages by LPS can be obtained in the presence of 4 mM EGTA. NO synthase expression is thus controlled in primed macrophages by two different pathways; calcium ionophores can replace LPS but do not act through the same intracellular cascade.
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PMID:Role of calcium in the activation of mouse peritoneal macrophages: induction of NO synthase by calcium ionophores and thapsigargin. 750 25


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