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)

Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present article reviews our recent studies involving the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia and its role in the regulation of nitric oxide synthase (NOS)2 and heme oxygenase (HO)-1. COX-2-deficient (-/-) mice display a blunted and delayed induction of the cytokine-inducible genes NOS2 and HO-1 after administration of Escherichia coli lipopolysaccharide (LPS or endotoxin). Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor-kappaB and activating protein-1, are also reduced. In addition, COX-2(-/-) mice have reduced leukocyte infiltration into critical organs (kidneys and lungs) after LPS administration. Interestingly, the absence of COX-2 does not alter the LPS induction of several proinflammatory cytokines in tissue macrophages, but induction of the antiinflammatory cytokine interleukin-10 is exaggerated. After LPS administration, 50% of wild-type (+/+) mice die; however, COX-2(-/-) mice display a dramatic improvement in survival during endotoxemia. Taken together, our findings suggest that COX-2(-/-) mice are resistant to many of the detrimental consequences of endotoxemia.
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PMID:Alteration in heme oxygenase-1 and nitric oxide synthase-2 gene expression during endotoxemia in cyclooxygenase-2-deficient mice. 1534 45

Microglia are the immunoregulatory cells of the central nervous system (CNS) and share many characteristics with resident macrophages in extracerebral tissues. Nitric oxide (NO) is secreted by macrophages following induction of the NO synthase gene NOS2 by stimuli elicited during a T-cell response and/or by microbial products. NO regulates both innate and adaptive immune responses, such as killing intracellular pathogens and inhibiting T-cell proliferation. Regulation of NO production by microglia, however, is poorly understood. We find that microglia from healthy adult mice produce negligible amounts of NO compared with resident macrophages during restimulation of peptide-specific CD8 T cells, and therefore cannot block T-cell proliferation. The impaired NO response extends to exogenous NOS2-inducing stimuli, including cytokines, CD40 ligation, and lipopolysaccharide. In contrast, microglia produce proinflammatory cytokines in response to these same stimuli, and therefore possess a relatively selective block in NO production. We go on to show that resident microglia fail to produce detectable levels of either the NOS2 enzyme or NOS2 RNA in response to NO-inducing stimuli. We therefore propose that microglia in the healthy adult brain exist in an "NO-incompetent" state in which NO production is blocked at the level of NOS2 RNA. The inability of resident microglia in the healthy CNS to produce NO may allow these immunoregulatory cells to modulate immune processes temporally, and may serve to protect the CNS from irreparable damage at the onset of infection or injury.
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PMID:Resident microglia from adult mice are refractory to nitric oxide-inducing stimuli due to impaired NOS2 gene expression. 1537 54

A number of cell types express inducible nitric-oxide synthase (NOS2) in response to exogenous insults such as bacterial lipopolysaccharide or proinflammatory cytokines. Although it has been known for some time that the N-terminal end of NOS2 suffers a post-translational modification, its exact identification has remained elusive. Using radioactive fatty acids, we show herein that NOS2 becomes thioacylated at Cys-3 with palmitic acid. Site-directed mutagenesis of this single residue results in the absence of the radiolabel incorporation. Acylation of NOS2 is completely indispensable for intracellular sorting and .NO synthesis. In fact, a C3S mutant of NOS2 is completely inactive and accumulates to intracellular membranes that almost totally co-localize with the Golgi marker beta-cop. Likewise, low concentrations of the palmitoylation blocking agents 2-Br-palmitate or 8-Br-palmitate severely affected the .NO synthesis of both NOS2 induced in muscular myotubes and transfected NOS2. However, unlike endothelial NOS, palmitoylation of inducible NOS is not involved in its targeting to caveolae. We have created 16 NOS2-GFP chimeras to inspect the effect of the neighboring residues of Cys-3 on the degree of palmitoylation. In this regard, the hydrophobic residue Pro-4 and the basic residue Lys-6 seem to be indispensable for palmitoylation. In addition, agents that block the endoplasmic reticulum to Golgi transit such as brefeldin A and monensin drastically reduced NOS2 activity leading to its accumulation in perinuclear areas. In summary, palmitoylation of NOS2 at Cys-3 is required for both its activity and proper intracellular localization.
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PMID:Palmitoylation of inducible nitric-oxide synthase at Cys-3 is required for proper intracellular traffic and nitric oxide synthesis. 1548 46

Sepsis is a severe catabolic condition. The loss of skeletal muscle protein mass is characterized by enhanced release of the amino acids glutamine and arginine, which (in)directly affects interorgan arginine and the related nitric oxide (NO) synthesis. To establish whether changes in muscle amino acid and protein kinetics are regulated by NO synthesized by nitric oxide synthase-2 or -3 (NOS2 or NOS3), we studied C57BL6/J wild-type (WT), NOS2-deficient (NOS2-/-), and NOS3-deficient (NOS3-/-) mice under control (unstimulated) and lipopolysaccharide (LPS)-treated conditions. Muscle amino acid metabolism was studied across the hindquarter by infusing the stable isotopes L-[ring-2H5]phenylalanine, L-[ring-2H2]tyrosine, L-[guanidino-15N2]arginine, and L-[ureido-13C,2H2]citrulline. Muscle blood flow was measured using radioactive p-aminohippuric acid dilution. Under baseline conditions, muscle blood flow was halved in NOS2-/- mice (P < 0.1), with simultaneous reductions in muscle glutamine, glycine, alanine, arginine release and glutamic acid, citrulline, valine, and leucine uptake (P < 0.1). After LPS treatment, (net) muscle protein synthesis increased in WT and NOS2-/- mice [LPS vs. control: 13 +/- 3 vs. 8 +/- 1 (SE) nmol.10 g(-1).min(-1) (WT), 18 +/- 5 vs. 7 +/- 2 nmol.10 g(-1).min(-1) (NOS2-/-); P < 0.05 for LPS vs. control]. This response was absent in NOS3-/- mice (LPS vs. control: 11 +/- 4 vs. 10 +/- 2 nmol.10 g(-1).min(-1)). In agreement, the increase in muscle arginine turnover after LPS was also absent in NOS3-/- mice. In conclusion, disruption of the NOS2 gene compromises muscle glutamine release and muscle blood flow in control mice, but had only minor effects after LPS. NOS3 activity is crucial for the increase in muscle arginine and protein turnover during early endotoxemia.
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PMID:NOS3 is involved in the increased protein and arginine metabolic response in muscle during early endotoxemia in mice. 1564 57

Interleukin-1 beta (IL-1beta) is one of the main cytokines involved in the inflammatory response; it has multiple effects that can contribute to cell damage, one of which is the upregulation of the inducible form of nitric oxide (NO) synthase (NOS2) in certain cell types. We demonstrated previously that in vivo, cortical microglial inflammatory responses were increased when noradrenaline (NE) levels were depleted, suggesting that NE can reduce microglial activation. In the present report, we examined the role of IL-1beta in neurotoxicity induced by microglial-conditioned media, and possible neuroprotective effects of NE. Incubation of cortical neurons with conditioned media (CM) obtained from lipopolysaccharide (LPS)-treated microglia induced neuronal NOS2 expression and increased neuronal cell death, and these responses were reduced if the neurons were coincubated with interleukin-1 receptor antagonist. Cotreatment of microglial cells with LPS plus NE potently blocked IL-1beta production and reduced the ability of the CM to induce neuronal NOS2 and cell death. These results suggest that microglial release of IL-1beta is an important activator of neuronal inflammatory responses, and that protective effects of NE upon neurons involve a reduction of microglial-derived IL-1beta.
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PMID:Norepinephrine protects cortical neurons against microglial-induced cell death. 1594 76

The authors previously showed that conditioned media (CM) from activated microglia increased inducible nitric oxide synthase (NOS2) in cortical neurons. Here they examined the ability of noradrenaline (NA) to reduce neuronal NOS2 or cell death. Primary mouse cortical neurons were activated using CM from microglia incubated with lipopolysaccharide (LPS). Neuronal NOS2 was assessed by increases in nitrite accumulation, and increases in NOS2 mRNA levels and fluorescence of the NO-sensitive probe DAF-2 DA. NOS2 induction was associated with an increase in neuronal LDH release. When NA was added during microglial activation, neuronal NOS2 was significantly reduced (by approximately 70%); in contrast if NA was added to the neurons along with CM, there was less reduction (about 35% decrease) in NOS2 expression. NA added to either microglia or to neurons reduced neuronal LDH release comparably. Pretreatment of CM with blocking antibody to TNFalpha, alone or with IL1-receptor antagonist, partially reduced neuronal cell death and NOS2. Incubation of neurons with NA increased IkBalpha, which could reduce NOS2. These results demonstrate that NA modulates neuronal NOS2 expression and damage, and that these effects are primarily due to inhibition of microglia released factors. Perturbations of NA could exacerbate neuronal damage by allowing for increased inflammatory responses.
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PMID:Effects of noradrenaline on neuronal NOS2 expression and viability. 1677 78

Application of delta-aminolevulinic acid (ALA) results in the endogenous accumulation of protoporphyrin IX and is a useful approach in the photodynamic therapy (PDT) of cancers. To investigate the role of nitric oxide (NO) in the specific accumulation of protoporphyrin and ALA-induced PDT of cancerous cells, we transfected inducible-nitric oxide synthase (NOS2) cDNA into human embryonic kidney (HEK) 293T cells and examined the ALA-induced photo-damage as well as the accumulation of porphyrin in the cells. When the NOS2-expressing HEK293T cells were treated with ALA and then exposed to visible light, they became more sensitive to the light with accumulating porphyrins, as compared with the ALA-treated control cells. An increase in the generation of NO in transfected cells led to the accumulation of protoporphyrin with a concomitant decrease of ferrochelatase, the final step enzyme of heme biosynthesis. When mouse macrophage-like RAW264.7 cells were cultured with lipopolysaccharide and interferon-gamma, the expression of NOS2 was induced. The addition of ALA to these cells led to the accumulation of protoporphyrin and cell death upon exposure to light. The treatment of cells with an NOS inhibitor, NG-monomethyl-L-arginine acetate, resulted in the inhibition of protoporphyrin accumulation and cell death. The levels of mitochondrial ferrochelatase and rotenone-sensitive NADH dehydrogenase in the NOS2-induced cells decreased. These results indicated that the generation of NO augments the ALA-induced accumulation of protoporphyrin IX and subsequent photo-damage in cancerous cells by decreasing the levels of mitochondrial iron-containing enzymes. Based on the fact that the production of NO in cancerous cells is elevated, NO in the cells is responsible for susceptibility with ALA-induced PDT.
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PMID:The role of nitric oxide in delta-aminolevulinic acid (ALA)-induced photosensitivity of cancerous cells. 1719 60

Recent reports suggest the potential role of toll-like receptor 4 (TLR4) in initiation of inflammatory responses and fatty acid-induced insulin resistance. We describe here the synthesis of pro-inflammatory products in 3T3-L1 preadipocyte cell line after stimulation with lipopolysaccharide (LPS), a TLR4 agonist. Expression profiles of mRNA coding for IL6, CCL2, CCL5, CCL11, NOS2, and PTGS2 demonstrated a higher responsiveness to LPS of these transcripts in preadipocytes than in fully differentiated adipocytes, confirming inflammatory features of preadipocytes. IL6, CCL2, CCL5 and CCL11 were secreted in 3T3-L1 supernatants within 4 h after LPS stimulation. In addition, continuous exposure to LPS during adipocyte differentiation impaired this process as was demonstrated by analysis of mRNA profiles of lipogenesis enzymes (FABP4, GPD1, LPL), adipokines (adiponectin, resistin, visfatin, leptin), and of the transcription factor PPARgamma. This suggests that toll-like receptor mediated activation could regulate maintenance of preadipocyte status, and inflammatory environment encountered in inflamed white adipose tissue.
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PMID:Preadipocyte response and impairment of differentiation in an inflammatory environment. 1738 12

We previously demonstrated that tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS) downregulate aryl hydrocarbon receptor (AhR)-regulated genes, such as cytochrome P450 1a1 (Cyp1a1) and NADPH: quinone oxidoreductase 1 (Nqo1) gene expression, yet the mechanisms involved remain unknown. The correlation between the inflammation-mediated suppression of AhR-regulated genes and the TNF-alpha or LPS-induced nitric oxide (NO) production especially in murine hepatoma Hepa 1c1c7 cells has been questioned; therefore we investigated whether NO is involved in the modulation of Cyp1a1 and Nqo1 by TNF-alpha or LPS in Hepa 1c1c7 cells. A significant dose-dependent increase in the inducible nitric oxide synthase (NOS2) expression and NO production were observed by various concentrations of TNF-alpha (1, 5, and 10 ng/mL) and LPS (1 and 5 microg/mL) which was completely inhibited by a NOS2 inhibitor, L-N6-(1-iminoethyl) lysine (L-NIL) (1 mM). Furthermore, TNF-alpha and LPS significantly induced NOS2 expression. Both TNF-alpha and LPS repressed the beta-naphthoflavone (betaNF)-mediated induction of Cyp1a1 and Nqo1 at mRNA and activity levels. The downregulation of Cyp1a1, but not Nqo1, was significantly prevented by L-NIL. However, proxynitrite decomposer, iron tetrakis (N-methyl-4'-pyridyl) porphyrinato (FeTMPyP) (5 microM) did not affect TNF-alpha- and LPS-mediated downregulation of Cyp1a1 and Nqo1 at mRNA and activity levels. These results show that NO, but not peroxynitrite, may be involved in TNF-alpha- and LPS-mediated downregulation of Cyp1a1 without affecting the downregulation of Nqo1.
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PMID:Role of nitric oxide in downregulation of cytochrome P450 1a1 and NADPH: Quinone oxidoreductase 1 by tumor necrosis factor-alpha and lipopolysaccharide. 1758 58

Skeletal muscle demonstrates great plasticity in response to environmental and hormonal factors including pathogen-associated molecules, inflammatory cytokines, and growth factors. These signals impinge on muscle by forcing individual muscle fibers to either grow or atrophy. We recently demonstrated that skeletal muscle cells express multiple Toll-like receptors (TLR) that recognize bacterial cell wall components, such as lipopolysaccharide (LPS). Exposure of myocytes to LPS and other TLR ligands initiates an inflammatory response culminating in the autocrine production of cytokines and NO by NO synthase (NOS)2. The TLR signal through protein kinases that phosphorylate and promote the degradation of an inhibitory protein that normally retains the transcription factor, nuclear factor kappaB (NFkappaB), in the cytoplasm. Phosphorylation and degradation of the inhibitor of NFkappaB allows for translocation of NFkappaB to the nucleus and activation of inflammatory genes. Overexpression of a constitutively active inhibitor of NFkappaB kinase in skeletal muscle causes severe wasting, and we found that inhibitors of either the phosphorylation of IkappaB or its proteolytic degradation prevent TLR ligand-induced expression of cytokines and NOS2. The combination of LPS and interferon gamma dramatically enhances the magnitude and duration of LPS-stimulated NOS2 expression and reduces protein translation. Lipopolysaccharide and interferon gamma also downregulates signaling from the mammalian target of rapamycin, a kinase that directs changes in cell size. Inhibitors of NOS block the fall in muscle cell protein synthesis and restore translational signaling, indicating that activation of the NOS2-NO pathway is responsible for the observed decrease in muscle protein synthesis. Our work provides a molecular explanation for reduced muscle growth during infection. Muscle is largely self-sufficient because it expresses receptors, signaling pathways, and effectors to regulate its own size. Prolonged activation of NFkappaB and NOS2 have emerged as detrimental facets of the immune response in muscle. The interplay between inflammatory components and growth factor signaling clearly places muscle at the interface between growth and immunity.
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PMID:Regulation of muscle growth by pathogen-associated molecules. 1819 60

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