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)

Increased gut permeability (leaky gut) and endotoxin-mediated Kupffer cell activation are proposed as the mechanisms of alcoholic liver injury. Although ethanol feeding is shown to sensitize the liver for injury induced by parental administration of lipopolysaccharide (LPS), how enteral LPS loading affects alcoholic liver injury is yet to be tested. The present study provides direct evidence for enhanced entrance to portal circulation of LPS enterally administered to the intragastric ethanol infusion model. Portal and systemic blood endotoxin levels increased to 43.0 +/- 4.1 and 6.2 +/- 4.3 pg/mL at 2 hours following enteral LPS administration (5 mg/kg) in alcohol-fed animals, while no such increases were observed in pair-fed controls. However, endotoxin levels in systemic blood of alcohol-fed rats were reduced to 0 to 1. 5 pg/mL 16 hours after LPS administration. Weekly enteral administration of LPS to the model for 9 weeks exacerbated an increase in plasma alanine transaminase (ALT) levels (227 +/- 75 vs. 140 +/- 70; P <.01), mononuclear infiltration (25 +/- 22 vs. 6.4 +/- 4.4/10 mm(2); P =.02), sinusoidal congestion, and spotty necrosis, and induced diffuse coagulative necrosis and centrilobular fibrosis in some animals. Reverse-transcription polymerase chain reaction (RT-PCR) analysis confirmed the LPS effect at the tissue level by demonstrating accentuated induction of tumor necrosis factor alpha (TNF-alpha) and Cox-2 mRNA. In conclusion, enteral LPS administration potentiates alcoholic liver necrosis, inflammation, and fibrosis despite efficient endotoxin clearance by the liver and mild systemic endotoxemia that occurs episodically following enteral LPS challenge.
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PMID:Exacerbation of alcoholic liver injury by enteral endotoxin in rats. 1105 51

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used to ameliorate neutropenia in patients after antineoplastic treatment. It has also been suggested as an adjunct treatment in septic patients; however, the recruitment and priming of leukocytes by GM-CSF bears the hazard of a hyperinflammatory response. In particular, the role of GM-CSF in pulmonary functions in septic lungs is still unclear. Therefore, we pretreated rats in vivo with GM-CSF (50 microg/kg, intravenous) and assessed the pulmonary functions of their subsequently prepared isolated perfused lungs when exposed to subtoxic concentrations of lipopolysaccharide (LPS, 2 microg/ml). These lungs showed enhanced expression of cyclooxygenase 2 (COX-2), a significant increase in thromboxane (TX) and tumor necrosis factor (TNF) release into the venous perfusate, and bronchoconstriction. COX-2 inhibition or blocking of the TX receptor abolished the GM-CSF/LPS-induced bronchoconstriction, but not the TNF release. Neutralizing antibodies against TNF did not prevent GM-CSF/LPS-induced bronchoconstriction. After GM-CSF pretreatment, massive neutrophil invasion into the lung occurred. Neutropenic rats were protected against GM-CSF/ LPS-induced lung injury. Similar results were obtained in rats pretreated with G-CSF instead of GM-CSF. We conclude that GM-CSF pretreatment exacerbates pulmonary injury by low-dose LPS via COX-2 expression, TX release, and bronchoconstriction by initiating neutrophil invasion and activation.
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PMID:Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil- and cyclooxygenase 2-dependent mechanism. 1117 20

A decrease and subsequent increase in nociceptive threshold in the whole body are clinical symptoms frequently observed during the course of acute systemic infection. These biphasic changes in nociceptive reactivity are brought about by central signal substances induced by peripheral inflammatory messages. Systemic administration of lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta), an experimental model of acute infection, may mimic the biphasic changes in nociception, hyperalgesia at small doses of LPS, and IL-1 beta and analgesia at larger doses. Our behavioral and electrophysiological studies have revealed that IL-1 beta in the brain induces hyperalgesia through the actions of prostaglandin E2 (PGE2) on EP3 receptors in the preoptic area and its neighboring basal forebrain, whereas the IL-1 beta-induced analgesia is produced by the actions of PGE2 on EP1 receptors in the ventromedial hypothalamus. An intravenous injection of LPS (10-100 micrograms/kg) produced hyperalgesia only during the period before fever develops and was abolished by microinjection of NS-398 (an inhibitor of cyclooxygenase 2) into the preoptic area, but not into the other areas in the hypothalamus. The hyperalgesia induced by the cytokines PGE2 and LPS may explain the systemic hyperalgesia clinically observed in the early phase of infectious diseases, which probably warns the organisms of infection before the full development of sickness symptoms. The switching of nociception from hyperalgesia to analgesia accompanied by sickness symptoms may reflect changes in the host's strategy for fighting microbial invasion as the disease progresses.
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PMID:Hypothalamic mechanisms of pain modulatory actions of cytokines and prostaglandin E2. 1126 35

Sulforaphane (SFN), an aliphatic isothiocyanate, is a known cancer chemopreventive agent. Aiming to investigate anti-inflammatory mechanisms of SFN, we here report a potent decrease in lipopolysaccharide (LPS)-induced secretion of pro-inflammatory and pro-carcinogenic signaling factors in cultured Raw 264.7 macrophages after SFN treatment, i.e. NO, prostaglandin E(2), and tumor necrosis factor alpha. SFN did not directly interact with NO, nor did it inhibit inducible nitric-oxide synthase enzymatic activity. Western blot analyses revealed time- and dose-dependent reduction of LPS-induced inducible nitric-oxide synthase as well as Cox-2 protein expression, which was suppressed at the transcriptional level. To reveal the target of SFN beyond its anti-inflammatory action, we performed electrophoretic mobility shift assay analyses of transcription factor-DNA binding. Consequently, nuclear factor kappa B (NF-kappa B), a pivotal transcription factor in LPS-stimulated pro-inflammatory response, was identified as the key mediator. SFN selectively reduced DNA binding of NF-kappa B without interfering with LPS-induced degradation of the inhibitor of NF-kappa B nor with nuclear translocation of NF-kappa B. Because SFN can interact with thiol groups by dithiocarbamate formation, it may impair the redox-sensitive DNA binding and transactivation of NF-kappa B. Sulforaphane could either directly inactivate NF-kappa B subunits by binding to essential Cys residues or interact with glutathione or other redox regulators like thioredoxin and Ref-1 relevant for NF-kappa B function. Our data provide novel evidence that anti-inflammatory mechanisms contribute to sulforaphane-mediated cancer chemoprevention.
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PMID:Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. 1141 May 99

Depending on sequence, bacterial and synthetic DNAs can activate the host immune system and influence the host response to infection. The purpose of this study was to determine the abilities of various phosphorothioate oligonucleotides with cytosine-guanosine-containing motifs (CpG DNA) to activate macrophages to produce nitric oxide (NO) and prostaglandin E(2) (PGE(2)) and to induce expression of NO synthase 2 (NOS2) and cyclooxygenase 2 (COX2). As little as 0.3 microg of CpG DNA/ml increased NO and PGE(2) production in a dose- and time-dependent fashion in cells of the mouse macrophage cell line J774. NO and PGE(2) production was noted by 4 to 8 h after initiation of cultures with the CpG DNA, with the kinetics of NO production induced by CpG DNA being comparable to that induced by a combination of lipopolysaccharide and gamma interferon. CpG DNA-treated J774 cells showed enhanced expression of NOS2 and COX2 proteins as determined by immunoblotting, with the relative potencies of the CpG DNAs generally corresponding to those noted for the induction of NO and PGE(2) production as well as to those noted for the induction of interleukin-6 (IL-6), IL-12, and tumor necrosis factor. Extracts from CpG DNA-treated cells converted L-arginine to L-citrulline, but the NOS inhibitor N(G)-monomethyl-L-arginine (NMMA) inhibited this reaction. The COX2-specific inhibitor NS398 inhibited CpG DNA-induced PGE(2) production and inhibited NO production to various degrees. The NOS inhibitors NMMA, 1400W, and N-iminoethyl-L-lysine effectively blocked NO production and increased the production of PGE(2) in a dose-dependent fashion. Thus, analogues of microbial DNA (i.e., CpG DNA) activate mouse macrophage lineage cells for the expression of NOS2 and COX2, with the production of NO and that of PGE(2) occurring in an interdependent manner.
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PMID:Host response to infection: the role of CpG DNA in induction of cyclooxygenase 2 and nitric oxide synthase 2 in murine macrophages. 1170 51

Genetic evidence that Toll-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor and biochemical evidence that Tlr4 confers LPS responsiveness as determined by activation of NF-kappaB and expression of inducible cyclooxygenase 2 have been demonstrated. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. It is now demonstrated that SFAs, but not unsaturated fatty acids (UFAs), induce NF-kappaB activation and expression of COX-2 and other inflammatory markers in macrophages. UFAs inhibit COX-2 expression induced by SFAs and LPS. Additional evidence suggests that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Whether fatty acids also modulate signaling pathways and target gene expression derived from the activation of other Tlrs remains to be determined.-Hwang, D. Modulation of the expression of cyclooxygenase 2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways.
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PMID:Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways. 1172 30

Kupffer cells are involved in the pathogenesis of chemically mediated liver injury through release of biologically active mediators that promote the pathogenic process. The purpose of this study was to elucidate specific biochemical and molecular changes occurring in Kupffer cells throughout a time course of carbon tetrachloride (CCl(4))-mediated liver injury and fibrosis. Rats were administered 1 ml/kg of CCl(4) (10% v/v olive oil) twice weekly for up to 6 weeks. Plasma alanine aminotransferase values and hematoxylin-and-eosin- and trichrome-stained liver sections indicated minor liver damage at 2 weeks followed by increased damage and collagen deposition by 4 and 6 weeks. Additionally, mRNA levels in Kupffer cells isolated from CCl(4)-treated rats demonstrated significant increases in tumor necrosis factor alpha (TNF alpha); tumor growth factor beta; interleukin-6 (IL-6); interleukin 1 beta; cyclooxygenase 2; CD14, and I kappa B alpha transcripts after 2 and 4 weeks of treatment. However, the expression of these genes at 6 weeks was similar to that of controls. Increased gene expression of cytokines in Kupffer cells isolated from CCl(4)-treated rats was accompanied by increases in protein production of TNF alpha, IL-6, IL-1 beta, and interleukin 10 following lipopolysaccharide stimulation. Further, liver sections stained for ED2-positive cells demonstrated an increase in the number of resident macrophages at 2 and 4 weeks with a slight decrease in ED2-positive cells by week 6 but still significantly more than control. Analysis of reduced glutathione (GSH) and oxidized glutathione (GSSG) indicated that Kupffer cells from CCl(4)-treated animals exhibited a 50% decrease in GSH at 2 and 4 weeks, whereas no significant changes were observed for GSSG. In conclusion, these data implicate Kupffer cells as a critical mediator of the inflammatory and fibrogenic responses during CCl(4)-mediated liver damage and provide new insight into the temporal molecular and biochemical changes associated with the ability of these resident macrophages to modulate liver injury.
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PMID:Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. 1173 48

We cloned the cDNA for mouse microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and expressed the recombinant enzyme in Escherichia coli. The membrane fraction containing recombinant mPGES-1 catalyzed the isomerization of PGH2 to PGE2 in the presence of GSH with K(m) values of 130 microM for PGH2 and 37 microM for GSH, a turnover number of 600 min(-1), and a k(cat)/K(m) ratio of 4.6 min(-1) microM(-1). Recombinant mPGES-1 was purified and used to generate a polyclonal antibody highly specific for mPGES-1. The antibody showed a single band on Western blotting of microsomal fractions from lipopolysaccharide-treated mouse peritoneal macrophages. Northern and Western blotting analyses revealed that mPGES-1 was induced together with cyclooxygenase-2 in mouse macrophages after treatment of the cells with lipopolysaccharide. Confocal immunofluorescence microscopy revealed that both mPGES-1 and cyclooxygenase-2 were colocalized in the lipopolysaccharide-treated macrophages. Taken together, these results demonstrate that mPGES-1 is an efficient downstream enzyme for the production of PGE2 in the activated macrophages treated by lipopolysaccharide.
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PMID:Biochemical characterization of mouse microsomal prostaglandin E synthase-1 and its colocalization with cyclooxygenase-2 in peritoneal macrophages. 1179 91

Human alveolar macrophages have both lipopolysaccharide (LPS)-induced and constitutive phosphatidylinositol 3-kinase (PI3K) activity. We observed that blocking PI3K activity increased release of prostaglandin E2 after LPS exposure, and increasing PI3K activity (interleukin-13) decreased release of prostaglandin E2 after LPS exposure. This was not because of an effect of PI3K on phospholipase 2 activity. PI3K inhibition resulted in an increase in cyclooxygenase 2 (COX2) protein, mRNA, and mRNA stability. PI3K negatively regulated activation of the p38 pathway (p38, MKK3/6, and MAPKAP2), and an active p38 was necessary for COX2 production. The data suggest that PI3K inhibition of p38 modulates COX2 expression via destabilization of LPS-induced COX2 mRNA.
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PMID:Phosphatidylinositol 3-kinase activity negatively regulates stability of cyclooxygenase 2 mRNA. 1207 39

The RON receptor tyrosine kinase is activated by macrophage-stimulating protein, which regulates macrophage migration, phagocytosis, and nitric oxide production. We report here the inhibitory effect of RON on lipopolysaccharide (LPS)-induced cyclooxygenase (Cox)-2 expression in mouse macrophages. In RON-expressing macrophages treated with macrophage stimulating protein, LPS-induced prostaglandin E(2) (PGE(2)) production was significantly reduced. The inhibition was accompanied by reduction of Cox-2 protein and mRNA expression. Transcriptional studies indicated that RON activation inhibits LPS-induced luciferase activity driven by the Cox-2 gene promoter. To determine whether RON activation affects LPS-induced NF-kappa B pathway, which is important for Cox-2 expression. Western blot analyses were performed showing that RON activation inhibits LPS-induced I kappa B alpha degradation. The decreased I kappa B alpha degradation was due to reduced I kappa B alpha phosphorylation at Ser-32 as determined by I kappa B alpha (Ser-32) phosphor-antibody. Moreover, we found that LPS-induced IKK beta activity, an enzyme responsible for phosphorylation of I kappa B alpha, was inhibited upon RON activation. Interestingly, these inhibitory effects were not regulated by RON-mediated phosphatidylinositol-3 kinase. These results suggest that RON activation inhibits LPS-induced macrophage Cox-2 expression. The inhibitory effect is mediated by impairing LPS-activated cascade enzymes that activate NF-kappa B. The inhibition of Cox-2 expression might represent a novel mechanism for the inhibitory functions of RON in vivo against LPS-induced inflammation and septic shock.
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PMID:Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. 1217 64


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