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)

Nitric oxide synthase (NOS) catalyzes the production of nitric oxide (NO), a short-lived radical gas with physiological or pathophysiological roles in nearly every organ system. The inducible NO synthase (iNOS) is a high-output isoform compared to the two constitutive NOSs. The iNOS from murine macrophages tightly binds calmodulin as a subunit, and its activity is not dependent on exogenous calmodulin or elevated calcium. This iNOS is induced at the transcriptional level by bacterial lipopolysaccharide (LPS) and interferon-gamma. The promoter region of the murine iNOS gene contains at least 24 oligonucleotide motifs corresponding to elements involved in the binding of transcription factors in the promoters of other cytokine-inducible genes. Nuclear factor NF-kappa B/c-rel, interacting with cycloheximide-sensitive protein(s) and binding to the NF-kappa Bd site in the iNOS promoter, controls the induction of iNOS by LPS. However, iNOS is also regulated posttranscriptionally. Complex regulation of iNOS at multiple levels may reflect the dual role of iNOS in host defense and autotoxicity.
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PMID:The high-output nitric oxide pathway: role and regulation. 752 16

Renal proximal tubules isolated from the rat possess nitric oxide synthase (NOS) activity that is calcium/calmodulin dependent and stereoselectively inhibited by NG-monomethyl-arginine (NMMA). In the absence of added Ca2+ and calmodulin, activity was reduced 84 +/- 13% compared with the activity in the presence of 2 mM Ca2+ and 25 micrograms/mL calmodulin. Inhibition by EGTA (10 mM) was 95 +/- 5% and by calmidazolium (R24571, 250 microM) was 99 +/- 1%. Inhibition by L-NMMA (100 microM) was 78 +/- 13% and by D-NMMA (100 microM) was 7 +/- 7%. The majority of NOS activity was found in the soluble fraction. NOS activity in isolated proximal tubules was also examined 6 hr after a single i.v. injection of lipopolysaccharide. Activity was increased significantly (P < 0.05) in the soluble fraction by 2-fold [from 0.320 +/- 0.052 to 0.648 +/- 0.046 (nmol/mg protein/30 min)] and in the particulate fraction by 3-fold [from 0.081 +/- 0.030 to 0.256 +/- 0.034 (nmol/mg protein/30 min)]. All activities were inhibited by EGTA. These data demonstrate that proximal tubules express a calcium/calmodulin-dependent NOS activity that is increased in vivo by lipopolysaccharide.
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PMID:Effect of lipopolysaccharide on nitric oxide synthase activity in rat proximal tubules. 753 Sep 53

Nitric oxide (NO) synthase activity was detected in fat body and the Malpighian tubles of the silkworm, Bombyx mori. Main NO synthase activity in the fat body was Ca(2+)/calmodulin-dependent, inducible by bacterial lipopolysaccharide (LPS) and required NADPH, FAD, FMN, dithiothreitol (DTT) and tetrahydrobiopterin (BH4) as cofactors for the full expression of the activity. The Malpighian tubles contained two types of NO synthase. One was Ca(2+)-independent, calmodulin-dependent and constitutive and the other was Ca(2+)-dependent and constitutive. The former NO synthase required the same cofactors as fat body NO synthase. The activity of Malpighian tuble NO synthases increased dramatically at the end of the last instar period, just prior to spinning. These results indicate that B. mori contains new types of NO synthase, suggesting the wide distribution and different characteristics of this enzyme among vertebrates and invertebrates.
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PMID:Occurrence of novel types of nitric oxide synthase in the silkworm, Bombyx mori. 753 73

Substance P (SP) and lipopolysaccharide (LPS) stimulated interleukin-6 (IL-6) gene expression, as well as IL-6 protein secretion in the human astrocytoma cell line U373 MG. Staurosporine, an inhibitor of protein kinase C (PKC), entirely blocked SP- but not LPS-induced IL-6 release. In addition, the down regulation of PKC inhibited the SP response and only marginally altered LPS activation. Differently from SP, LPS-induced IL-6 release was markedly reduced by W7, a calmodulin antagonist. Moreover, SP interacted in a synergistic manner with LPS. Thus, neural (SP) and bacterial (LPS) mediators stimulate U373 MG IL-6 release via distinct, though not antagonistic, activation pathways.
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PMID:Interleukin-6 production by U373 MG, a human astrocytoma cell line: different pathways involved in substance P and lipopolysaccharide activation. 754 Oct 52

Immunohistochemical studies have shown expression of two different isoforms of NOS in the juxtaglomerular apparatus (JGA). Antibodies to a Ca(++)-calmodulin dependent isoform purified from rat brain (B-NOS) label the macula densa cells whereas antibodies to an isoform purified from rat aortic smooth muscle cells in culture (VSM-NOS) induced with lipopolysaccharide and interferon gamma label the afferent arteriole. Since dietary salt intake and angiotensin II (Ang II) are determinants of renal NO generation, we have tested the hypothesis that salt intake can regulate the immunohistochemical expression of these NOS isoforms through an effect of Ang II. In 4 of 5 paired studies, the immunostaining for both B-NOS and VSM-NOS was more intense in rats that had received a low salt (LS), compared to a high salt (HS), diet. Infusion of the Ang II type 1 (AT1) receptor antagonist, losartan, enhanced the intensity of immunoreactive staining for both isoforms. In conclusion, the immunohistochemical expression of NOS isoforms in the JGA is increased by dietary salt restriction; this effect cannot be ascribed to Ang II acting on type 1 receptors.
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PMID:Expression of immunoreactive nitric oxide synthase isoforms in rat kidney. Effects of dietary salt and losartan. 754 16

Nitric oxide is a short-lived biologic mediator for diverse cell types. Synthesis of an inducible nitric oxide synthase (NOS) in murine macrophages is stimulated by lipopolysaccharide (LPS) and interferon gamma. In human hepatocytes, NOS activity is induced by treatment with a combination of tumor necrosis factor, interleukin 1, interferon gamma, and LPS. We now report the molecular cloning and expression of an inducible human hepatocyte NOS (hep-NOS) cDNA. hep-NOS has 80% amino acid sequence homology to macrophage NOS (mac-NOS). Like other NOS isoforms, recognition sites for FMN, FAD, and NADPH are present, as well as a consensus calmodulin binding site. NOS activity in human 293 kidney cells transfected with hep-NOS cDNA is diminished by Ca2+ chelation and a calmodulin antagonist, reflecting a Ca2+ dependence not evident for mac-NOS. Northern blot analysis with hep-NOS cDNA reveals a 4.5-kb mRNA in both human hepatocytes and aortic smooth muscle cells following stimulation with LPS and cytokines. Human genomic Southern blots probed with human hep-NOS and human endothelial NOS cDNA clones display different genomic restriction enzyme fragments, suggesting distinct gene products for these NOS isoforms. hep-NOS appears to be an inducible form of NOS that is distinct from mac-NOS as well as brain and endothelial NOS isozymes.
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PMID:Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. 768 6

Intracellular protein phosphorylation is thought to be the initial step in cell activation. Bacterial lipopolysaccharide (LPS) induces a special set of the protein phosphorylation in the murine peritoneal macrophages, including p65 (molecular mass of 65 kDa) which is a substrate of serine kinase and the most dominant phosphorylated cytosolic protein. This article deals with the relation between the LPS-induced protein phosphorylation in the murine peritoneal macrophages and their productions of IL-1 beta and TNF-alpha. LPS-induced p65 phosphorylation seems to be dependent on protein kinase C (PKC) and calmodulin (CaM), because it diminishes in the presence of inhibitors to PKC or CaM. Tyrosine kinase inhibitors do not affect the p65 phosphorylation. The PKC inhibitors also affect the mRNA expressions and the productions of active molecules of IL-1 beta and TNF-alpha. Though the CaM inhibitor inhibits the mRNA expression and the active molecule production of IL-1 beta, it does not affect those of TNF-alpha. These results suggest that LPS-induced p65 phosphorylation is closely related to PKC and CaM, and that IL-1 beta production depends on PKC and CaM, while the TNF-alpha production is not dependent on CaM. These findings indicate the existence of multiple pathways and different regulatory mechanisms for transduction of LPS signal in the macrophages. Furthermore, LPS-induced phosphorylation is not observed in endotoxin tolerant macrophages after re-stimulation with LPS, suggesting that the LPS-stimulus signal is blocked at a site in the signal transduction-pathway before the point of phosphorylation of proteins in the tolerant macrophages.
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PMID:Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): effects of kinase-inhibitors and LPS-induced tolerance. 768 35

Calmodulin-dependent nitric-oxide synthase, with an apparent molecular mass of 125 kDa, was induced in the liver of rats treated with Propionibacterium acnes and Escherichia coli lipopolysaccharide. Clones were isolated from a cDNA library obtained from induced rat liver using oligonucleotide probes which were synthesized based on the amino acid sequences of peptides of the purified enzyme. Four overlapping cDNA clones for a 3.8-kbp region were isolated and the nucleotide sequences were determined. These clones encompassed an open-reading frame of 3441 bases encoding 1147 amino acids. The deduced amino acid sequence of the cDNA suggested that the protein contains binding sites for NADPH, FAD and FMN. The structure of the possible calmodulin-binding site, consisting of a strongly hydrophobic region surrounded by basic amino acids, is present. The full-length cDNA was expressed in COS 1 cells under the control of a cytomegalovirus promoter and the expressed enzyme was found to be a calmodulin-dependent nitric-oxide synthase. A structural comparison suggested that the liver nitric-oxide synthase is the same as the macrophage enzyme. Northern-blot analysis showed that the mRNA in the liver is approximately 4.2 kb long and is induced transcriptionally by treatment with P. acnes and lipopolysaccharide.
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PMID:Molecular cloning of a cDNA encoding an inducible calmodulin-dependent nitric-oxide synthase from rat liver and its expression in COS 1 cells. 769 62

1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3, calcitriol] has been shown to modulate the immune function of peripheral monocytes and peritoneal macrophages. However, its effect on alveolar macrophage (AM) cytokine secretion has not been reported. We therefore investigated the influence of calcitriol on tumor necrosis factor (TNF-alpha) production by murine AMs and attempted to elucidate changes in the signal transduction system involved in such effects. Calcitriol significantly enhanced TNF-alpha secretion by AM stimulated with either lipopolysaccharide (LPS; 10 micrograms/ml; p < 0.005) or phorbol 12-myristate 13-acetate (PMA; 100 ng/ml; p < 0.05) at low doses (between 10(-11) and 10(-9) M). However the protein kinase C (PKC) inhibitor, H7 (10 microM), and the Ca2+/calmodulin inhibitor, W7 (25 microM), reversed such calcitriol effects. Calcitriol increased the total PKC activity of AMs. These findings indicate that calcitriol enhances both LPS- and PMA-stimulated TNF-alpha secretion through PKC- or Ca2+/calmodulin-dependent pathways.
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PMID:Stimulatory effect of 1 alpha,25-dihydroxyvitamin D3 on mouse alveolar macrophage tumor necrosis factor-alpha production in vitro: involvement of protein kinase C and Ca2+/calmodulin-dependent kinase. 778 16

Tumour necrosis factor (TNF) plays a pivotal role in the induction of cerebral complications during Plasmodium falciparum malaria. TNF secretion by macrophages can be induced by lipopolysaccharide (LPS) and by P. falciparum antigens, but it is unclear whether similar mechanisms control the monokine expression in both cases. The signal transduction pathway by which parasite antigens induce TNF secretion remains to be established. The results reported here, using various inhibitors of second messenger pathways, clearly demonstrate that the signal transduction leading to TNF secretion is mediated partly through protein kinase C and calmodulin-dependent protein kinase activation. Furthermore, this signal seems to be differentially regulated after LPS or parasite stimulation, since cyclo-oxygenase inhibition by indomethacin resulted in twofold more TNF production enhancement with LPS stimulation than with parasite stimulation. The nature of the receptor involved in the parasite induced-macrophage stimulation remains obscure. However, the results discussed here indicate that parasite antigens stimulate multiple signal transduction pathways via G protein. Identification of the different pathways involved in these receptor-mediated events may be invaluable in the development of specific inhibitors against TNF over-production during cerebral malaria.
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PMID:Signal transduction pathways involved in tumour necrosis factor secretion by Plasmodium falciparum-stimulated human monocytes. 782 69


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