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)

CGP 47969A is a novel inhibitor of the biosynthesis of interleukin-1 and other cytokines, being developed as an anti-arthritic. The effect of the compound on lipopolysaccharide (LPS; 1 microgram/ml) stimulated nitric oxide (NO) production by the mouse macrophage cell line, J774A.1, was examined in the present study. CGP 47969A inhibited NO production in a concentration-dependent fashion (0.1-10 microM; IC50 = 2 microM) in a 24 h assay. Dexamethasone (Dex), which inhibits cytokine and inducible nitric oxide synthase (iNOS) gene transcription, and N-methyl arginine (NMA), a substrate analogue inhibitor of NOS activity, also inhibited NO production in this assay system with IC50 values of approximately 5 nM and 100 microM, respectively. When iNOS expression was induced by LPS for 24 h, CGP 47969A and Dex did not inhibit NO production, whereas NMA retained activity (IC50 = 40 microM). In time course experiments, CGP 47969A (10 microM) or Dex (1 microM) were added to J774A.1 cultures at t = 0, 1, 3 or 6 h after LPS. Dex inhibited NO production by 86%, 57%, 35% and 15% at these time points, while CGP 47969A inhibited by 90%, 91%, 89% and 76%. Taken together, the results indicate that CGP 47969A inhibits NO production by an effect similar to the inhibitory effect on cytokine production rather than by inhibition of iNOS enzyme activity per se or iNOS gene expression. The ability of CGP 47969A to inhibit cytokine and NO production may explain its efficacy in animal models of arthritis.
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PMID:Effects of the cytokine synthesis inhibitor CGP 47969A on nitric oxide production by lipopolysaccharide-stimulated J774A.1 macrophages. 774 Oct 43

The synthesis of nitric oxide by proximal tubule-inducible nitric oxide synthase requires tetrahydrobiopterin as a cofactor. To determine whether tetrahydrobiopterin synthesis is required for nitric oxide production, nitrite release by mouse proximal tubule cells treated with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of the rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin from guanosine triphosphate, guanosine triphosphate cyclohydrolase I, was measured. Treatment with lipopolysaccharide (0.1 micrograms/mL) and interferon-gamma (100 U/mL) for 12 h increased nitrite production from 2.7 +/- 0.2 to 25.4 +/- 1.3 nmol/mg of protein (P < 0.001; N = 9). 2,4-Diamino-6-hydroxypyrimidine (6 mM) reduced lipopolysaccharide/interferon-gamma-induced nitrite production by 53.1 +/- 3.4%. Sepiapterin, a substrate for tetrahydrobiopterin synthesis via the dihydrofolate reductase-dependent pterin salvage pathway, prevented the inhibition by 2,4-diamino-6-hydroxypyrimidine, an effect that was blocked by methotrexate. In conclusion, guanosine triphosphate cyclohydrolase I activity is required for cytokine-induced nitric oxide production by proximal tubular epithelium. The inhibition of guanosine triphosphate cyclohydrolase I could prove useful in the treatment of nitric oxide-mediated renal disorders.
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PMID:Guanosine triphosphate cyclohydrolase I regulates nitric oxide synthesis in renal proximal tubules. 775 97

We recently reported (Am. J. Respir. Cell Mol. Biol. 7: 471-476, 1992) that a mixture of lipopolysaccharide (LPS) and cytokines produced a time-dependent increase in mRNA and protein expression of inducible nitric oxide synthase (iNOS) in cultured rat pulmonary artery smooth muscle cells (RPASM). In the current study we extend observations on regulation of iNOS in RPASM by showing that de novo synthesis of tetrahydrobiopterin (BH4) is critical for LPS and cytokine-induced NO production. A mixture of LPS and the cytokines gamma-interferon, interleukin-1 beta, and tumor necrosis factor-alpha increased steady-state levels of mRNA of GTP-cyclohydrolase-I (GTP-CH), the rate-limiting enzyme in BH4 biosynthesis. Levels of mRNA to GTP-CH became detectable by 4 h, with further increases at 24 h by Northern blot analysis and reverse-transcriptase polymerase chain reaction. Total intracellular biopterin levels, undetectable under basal conditions, increased after 24 h exposure to LPS and cytokines (to 32.3 +/- 0.8 pmol/mg protein). LPS and cytokine-induced NO production, determined by nitrite concentrations in the medium, was decreased in a concentration-dependent manner by the GTP-CH inhibitor, 2,4-diamino-6-hydroxypyrimidine (DAHP) at 24 h. DAHP also inhibited completely the LPS- and cytokine-induced accumulation of intracellular biopterins. Sepiapterin, which supplies BH4 through a salvage pathway independent of GTP-CH, reversed the effect of DAHP on LPS and cytokine-induced NO production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tetrahydrobiopterin synthesis and inducible nitric oxide production in pulmonary artery smooth muscle. 780 62

The effects of bacterial lipopolysaccharide (LPS) on macrophage gene expression are mediated in part by its ability to induce activation of transcription factor NF-kappa B. We compared the ability of LPS-treated macrophages from Lpsn (LPS-responsive) C3H/HeN and Lpsd (LPS-hyporesponsive) C3H/HeJ mice to mobilize NF-kappa B by electrophoretic mobility shift assays with oligonucleotide probes containing a unique NF-kappa B sequence from the promoter of inducible nitric oxide synthase (iNOS). In response to ng/ml concentrations of LPS, this probe bound proteins that appeared rapidly in the nuclei of thioglycollate-elicited macrophages and bone marrow-derived macrophage cell lines from both Lpsn and Lpsd mice. Only in macrophages from Lpsn mice, however, was LPS able to induce iNOS or tumor necrosis factor alpha. NF-kappa B-containing DNA-protein complexes from Lpsd macrophages were formed in lesser amounts than from Lpsn macrophages but shared the same composition, insofar as they displayed the same electrophoretic mobilities and content of heterodimers of p50/RelA (p65) and p50/c-rel. Two conclusions emerge from these findings: (1) NF-kappa B activity alone is not sufficient for induction of certain LPS-responsive genes and (2) An LPS-response pathway involving activation of NF-kappa B is preserved in Lpsd mice. The inability of cells from Lpsd mice to induce gene expression in response to LPS thus cannot be attributed to inability to activate NF-kappa B.
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PMID:Macrophages derived from C3H/HeJ (Lpsd) mice respond to bacterial lipopolysaccharide by activating NF-kappa B. 782 69

Treatment of mice with Corynebacterium parvum induces chronic inflammation. This treatment followed by an injection of lipopolysaccharide (LPS) produces hepatic necrosis and death. We examined liver tissue by using electron paramagnetic resonance (EPR) spectroscopy and found that, in addition to the previously reported nonheme nitrosyl complexes, heme nitrosyl complexes were also formed. Hemoglobin nitrosyl complexes measured in the whole blood of mice treated with C. parvum were not increased after additional LPS treatment. However, this treatment significantly increased the heme nitrosyl complexes in the liver, whereas the nonheme nitrosyl complex concentration was unaffected. EPR signals from whole blood and liver tissues from mice treated with C. parvum and C. parvum + LPS were inhibited by prolonged treatment with NG-monomethyl-L-arginine (L-NMA). Nitric oxide (.NO) is known to bind to cytochrome P450 heme, and we consistently found a suppression of EPR signals attributable to ferric low-spin cytochrome P450/P420 peaks in the livers of mice treated with C. parvum and C. parvum + LPS. By performing analyses of EPR spectra obtained from hepatocytes exposed to .NO, we were able to unambiguously identify EPR signals attributable to cytochrome P420 and nonheme nitrosyl complexes in the livers of both treatments. Deconvolution of the composite in vivo EPR spectra indicated that hemoglobin nitrosyl complexes contributed weakly in the C. parvum livers, but threefold more in the C. parvum + LPS livers, suggesting that hemorrhage may have occurred. Experiments with L-NMA treatment revealed that this additional .NO production did not correlate with hepatic necrosis and onset of death. Immunoprecipitation of liver cytosols from C. parvum- and (C. parvum + LPS)-treated mice using an antibody against mouse inducible nitric oxide synthase showed that this enzyme was indeed present in the cytosolic fractions and was absent in those from control livers. Our novel detection of cytochrome P420 nitrosyl complex in vivo may be linked to any role of hepatic P450's functions during liver inflammation.
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PMID:Targets of nitric oxide in a mouse model of liver inflammation by Corynebacterium parvum. 784 Jun 29

Nitric oxide (NO) is an important effector molecule of the inflammatory response. It is synthesized by mesangial cells and has been proposed to contribute to glomerular injury in various disease states. We studied whether NO modulates extracellular matrix production in cultured rat mesangial cells. Stimulation of rat mesangial cell NO release with gamma-interferon and lipopolysaccharide resulted in reduced production of collagen (by 35%) fibronectin (by 48%) (P < 0.05). In contrast, laminin synthesis was enhanced two-fold by the same maneuver (P < 0.05). These changes were reversed by the addition of L-NAME, a selective inhibitor of inducible nitric oxide synthase. This is the first demonstration that NO regulates the synthesis of extracellular matrix by mesangial cells. The results indicate that increased renal production of NO in glomerular diseases may attenuate the production and accumulation of matrix proteins and limit the severity of glomerulosclerosis.
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PMID:Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. 785 53

Recent studies indicate that human macrophages lack a high-output inducible nitric oxide synthase (NOS) antimicrobial system. In the present study, microglial cells derived from fetal human versus neonatal mouse brain were compared in a coculture assay of human and murine neuronal cell injury. Neurotoxicity (reflected by lactate dehydrogenase release and impaired neuronal uptake of [3H] gamma-amino butyric acid) and nitric oxide (NO) production (assessed by measurement of nitrite) were observed only in cocultures containing interferon (IFN)-gamma-lipopolysaccharide (LPS)-stimulated murine microglia. Cultures of purified human fetal microglia, however, did produce low levels of NO upon stimulation with IFN-gamma-LPS. These findings support the proposal that human macrophages have an inefficient IFN-gamma-inducible NOS and suggest that in tissues, such as brain, this deficiency could be advantageous for neighboring cells.
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PMID:Nitric oxide production and neurotoxicity mediated by activated microglia from human versus mouse brain. 803 37

Following trauma and tissue injury, patients frequently suffer infections and septic complications. Tissue injury is associated with the induction of the hepatic acute-phase response, but how this phenotypic expression by hepatocytes influences their subsequent response to endotoxin (lipopolysaccharide, LPS) or inflammatory cytokines is unknown. We have shown that both rat and human hepatocytes maximally express the enzyme-inducible nitric oxide synthase (iNOS) in response to a combination of LPS and the cytokines tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), and interleukin-1. Furthermore, we have shown that the in vivo induction of the acute-phase response following tissue injury (hind limb turpentine injection) is not associated with hepatocyte iNOS expression. In this study, we show that the phenotypic change associated with the acute-phase response following tissue injury primes the hepatocyte to subsequently express iNOS in vitro in response to LPS alone as well as TNF and IFN-gamma. This expression of iNOS can be seen as early as 3 hr following the initial injury and lasts up to 24 hr. Early postinjury changes result in maximal expression following stimulation with TNF or IFN-gamma. Later (24 hr post-injury) changes reveal LPS to be the most potent inducer with as little as 0.01 microgram/ml LPS being required for iNOS mRNA expression. The in vivo correlate of tissue injury (turpentine injection) followed by sepsis (intraperitoneal LPS injection) resulted in a three- to fourfold rise in plasma levels of the stable end-products of nitric oxide production, nitrite, and nitrate (NO2- + NO3-), over levels seen in cases of sepsis alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Remote tissue injury primes hepatocytes for nitric oxide synthesis. 804 Nov 39

Nitric oxide is a short-lived reactive mediator that inhibits bone marrow (BM) cell proliferation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). The present studies show that nitric oxide also inhibits macrophage colony-stimulating factor (M-CSF)-induced growth of mouse BM cells, an effect that was dependent on the presence of an inflammatory mediator and blocked by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMA). Treatment of mice with the hematotoxicant benzene (800 mg/kg, intraperitoneally, two times per day, for 2 days) resulted in a significant increase in nitric oxide production by BM cells stimulated with lipopolysaccharide (LPS) and interferon gamma alone or in combination with M-CSF or GM-CSF. Cells from benzene-treated mice also displayed increased sensitivity to the growth-promoting effects of M-CSF and GM-CSF. These results suggest that benzene treatment of mice primes BM cells to inducers of nitric oxide. Northern blot analysis showed that this was, at least in part, caused by increased expression of mRNA for inducible nitric oxide synthase (iNOS). Surprisingly, treatment of mice with L-NMA was found to cause a depression in BM cell proliferation and to potentiate benzene-induced decreases in BM cellularity and increases in nitric oxide production. L-NMA administration also augmented nitric oxide production by BM cells. These data indicate that L-NMA is hematotoxic and suggest that it may have actions distinct from inhibition of nitric oxide synthase in the BM.
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PMID:Enhanced production of nitric oxide by bone marrow cells and increased sensitivity to macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF after benzene treatment of mice. 819 60

1. We have compared the effect of aminoguanidine with that of N omega-nitro-L-arginine methyl ester on isolated thoracic aortic rings obtained either from endotoxin (lipopolysaccharide, 10 mg/kg, i.v. for 3 h) or vehicle (saline) treated rats. 2. Administration of endotoxin for 3 h resulted in a hypotension and a significant reduction of pressor responses to norepinephrine (1 micrograms/kg, i.v.) in the anaesthetized rat. 3. In intact rings obtained from vehicle treated rats, aminoguanidine (0.3 and 1 mmol/L) had no significant effect on acetylcholine-induced relaxation (10(-9)-10(-5) mol/L), whereas N omega-nitro-L-arginine methyl ester (0.3 mmol/L and 1 mmol/L) abolished that response, suggesting that aminoguanidine does not inhibit the activity of constitutive nitric oxide synthase. 4. Relaxation induced by L-arginine (10(-6)-10(-2) mol/L) was competitively inhibited by both aminoguanidine (0.3 mmol/L) and N omega-nitro-L-arginine methyl ester (0.3 mmol/L) in endothelium-denuded aortic rings obtained from endotoxin treated rats. 5. Three hours of endotoxaemia was associated with an impairment of contraction to norepinephrine (10(-9)-10(-6) mol/L) in the endothelium-denuded aorta ex vivo. This hyporeactivity to norepinephrine was partially restored by treatment of the vessels either with aminoguanidine (0.3 mmol/L) or with N omega-nitro-L-arginine methyl ester (0.3 mmol/L) in vitro. 6. These results in isolated thoracic aortae of the rat reinforce that aminoguanidine is a selective inhibitor of the inducible nitric oxide synthase, whereas N omega-nitro-L-arginine methyl ester is a non-selective inhibitor of both the inducible and constitutive nitric oxide synthase.
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PMID:Comparison of responses to aminoguanidine and N omega-nitro-L-arginine methyl ester in the rat aorta. 854 78


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