Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that rat primary microglial cultures express the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and that several functions associated with the activation of these cells, including nitric oxide (NO) and tumor necrosis factor-alpha synthesis, are down-regulated by 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, two specific PPAR-gamma agonists. Here we demonstrate that microglial cells not only express a functionally active PPAR-gamma, but also synthesize large amounts of 15d-PGJ2 upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ2 and ciglitazone were equally effective in reducing microglial activation when used at 1-5 microm concentrations, 15d-PGJ2, but not of ciglitazone, reduced PGE2 production at low concentration (0.1 microm) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 microm). Interestingly, the inhibition of PGE2 production was achieved mainly through the inhibition of cycloxygenase-2 enzymatic activity, as the expression of this enzyme and that of the microsomal isoform of PGE synthase remained unaltered. These findings suggest that 15d-PGJ2 affects the functional state and the survival of activated microglia through mechanisms only in part dependent on PPAR-gamma and that the concentration of 15d-PGJ2 is crucial in determining the particular microglial function affected.
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PMID:15-deoxy-delta12,14-prostaglandin J2 regulates the functional state and the survival of microglial cells through multiple molecular mechanisms. 1453 56

Cot is a MAPK kinase kinase that has been implicated in cellular activation and proliferation. Here, we show that the addition of lipopolysaccharide (LPS) to RAW264 macrophages induces a 10-fold increase of endogenous Cot activity, measured as MAPK kinase kinase 1 activity. Taxol, but not phorbol 12-myristate 13-acetate (PMA), induces a similar activation of Cot. A tyrosine kinase activity is involved in Cot activation by LPS. 15-Deoxy-Delta12,14-prostaglandin J2, but not rosiglitazone, blocks Cot activation by LPS. Furthermore, 15-deoxy-Delta12,14-prostaglandin J2 also inhibited the LPS-induced Cot in vitro. However, 15-deoxy-Delta12,14-prostaglandin J2 does not inhibit MAPK kinase 1 or ERK1/ERK2 activation/phosphorylation induced by PMA and mediated by c-Raf. Considering these data, we propose that the inhibition of LPS-induced Cot activation is one mechanism by which 15-deoxy-Delta12,14-prostaglandin J2 acts as an anti-inflammatory.
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PMID:15-Deoxy-Delta12,14-prostaglandin J2 regulates endogenous Cot MAPK kinase kinase 1 activity induced by lipopolysaccharide. 1455 73

Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.
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PMID:A novel antipyretic action of 15-deoxy-Delta12,14-prostaglandin J2 in the rat brain. 1496 Jun 2

Septic shock is still the major cause of death in surgical intensive care units. Both gram-positive (G+) and gram-negative (G-) bacteria have been isolated in the blood of a large portion of septic patients, and these polymicrobial infections often have a higher mortality than infections due to a single organism. Cell wall fragments from G+ and G- bacteria synergise to cause shock and multiple organ dysfunction in vivo (G+/G- shock). Male Wistar rats were anaesthetised and received a coadministration of wall fragments from G+ and G- bacteria, Staphilococcus aureus (S. aureus) peptidoglycan [0.3 mg/kg, intravenously (i.v.)] and Escherichia coli (E. coli) lipopolysaccharide (1 mg/kg, i.v.) or vehicle (saline, 1 ml/kg, i.v.). G+/G- shock for 6 h resulted in an increase in serum levels of creatinine (indicator of renal dysfunction), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (gamma-GT), bilirubin (markers for hepatic injury and dysfunction) and creatine kinase (CK, an indicator of neuromuscular, skeletal muscle or cardiac injury). Pretreatment of rats with the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15d-prostaglandin J2 (0.3 mg/kg, i.v., 30 min prior to G+/G-) reduced the multiple organ injury/dysfunction caused by coadministration of peptidoglycan+lipopolysaccharide. The selective PPAR-gamma antagonist GW9662 (2-Chloro-5-nitrobenzanilide) (1 mg/kg, i.v., given 45 min prior to G+/G-) abolished the protective effects of 15d-prostaglandin J2. 15d- prostaglandin J2 did not affect the biphasic fall in blood pressure or the increase in heart rate caused by administration of peptidoglycan+lipopolysaccharide. The mechanism(s) of the protective effect of this cyclopentenone prostaglandin are-at least in part-PPAR-gamma dependent, as the protection afforded by 15d-prostaglandin J2 was reduced by the PPAR-gamma antagonist GW9662. We propose that 15d-prostaglandin J2 or other ligands for PPAR-gamma may be useful in the therapy of the organ injury associated with septic shock.
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PMID:15d-prostaglandin J2 reduces multiple organ failure caused by wall-fragment of Gram-positive and Gram-negative bacteria. 1536 8

A previous study has demonstrated that 15-deoxy-delta12,14-prostaglandin J2 (15d-PG J2) enhanced acute lung injury induced by lipopolysaccharide (LPS) in mice. The enhancement in acute lung injury by 15d-PG J2 was concomitant with the enhanced expression of interleukin-1beta and chemokines in the lung. However, other underlying mechanisms of this enhancement remain to be elucidated. Cyclooxygenase (COX)-2 has been reported to be involved in enhanced pulmonary permeability during acute lung injury. This study investigated the effects of 15d-PG J2 on COXs expressions in the lung in the presence or absence of LPS. ICR mice were divided into 4 experimental groups that intratracheally received vehicle, lipopolysaccharide (LPS: 125 microg/kg), 15d-PG J2 (1 mg/kg), or 15d-PG J2 + LPS. The expression of mRNA for both COX-1 and -2 in the lung was evaluated 4 h after the intratracheal administration. 15d-PG J2 enhanced the COX-2 mRNA expression in the presence of LPS. In contrast, 15d-PG J2 did not affect the COX-1 expression. These results suggest that the enhancing effects of 15d-PG J2 on LPS-induced acute lung injury might be explained, at least in part, by those on the lung expression of COX-2.
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PMID:Effects of 15-deoxy-delta12,14-prostaglandin J2 on the cyclooxygenase-2 expression in the murine lung in the presence of lipopolysaccharide. 1561 12

1. Previously, we have demonstrated that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) enhances acute lung injury induced by lipopolysaccharide (LPS) in mice. The enhancement in acute lung injury by 15d-PGJ2 was concomitant with the enhanced expression of several pro-inflammatory cytokines in the lung. However, other underlying mechanisms of this enhancement remain to be elucidated. The present study investigated the effects of 15d-PGJ2 on the expression of Toll-like receptor (TLR) 4 and 2 in the lung in the absence or presence of LPS. 2. In the present study, ICR mice were divided into four experimental groups that received (intratracheally) vehicle, LPS (125 microg/kg), 15d-PGJ2 (1 mg/kg) or 15d-PGJ2 + LPS. The mRNA expression of both TLR4 and 2 in the lung was evaluated 4 h after intratracheal administration. 3. 15-Deoxy-Delta12,14-prostaglandin J2 enhanced the mRNA expression of both TLR4 and 2 in the presence of LPS. 4. These results suggest that the enhancing effects of 15d-PGJ2 on LPS-induced acute lung injury may be explained, at least in part, by its effect on the lung expression of TLR4 and 2.
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PMID:Effects of 15-deoxy-Delta12,14-prostaglandin J2 on the expression of Toll-like receptor 4 and 2 in the murine lung in the presence of lipopolysaccharide. 1574 8

15-Deoxy-delta(12, 14)-prostaglandin J2 (15d-PG J2) is a regulator of a nuclear transcriptional factor, peroxisome proliferator-activated receptor (PPAR)-gamma. A previous study has demonstrated that 15d-PG J2 enhanced acute lung injury induced by lipopolysaccharide (LPS) in mice. 15d-PG J2 induced mucin-producing cells in the bronchial epithelium, especially in the presence of LPS. The present study investigated the effects of 15d-PG J2 on the activation of GATA-3 and Signal Transducer and Activator of Transcription (STAT) 6, important transcriptional factors in mucus secretion, in the lung in the presence or absence of LPS. ICR mice were divided into 4 experimental groups that intratracheally received vehicle, lipopolysaccharide (LPS: 125 microg/kg), 15d-PG J2 (1 mg/kg), or 15d-PG J2 + LPS. The nuclear localization of GATA-3 and phosphorylated STAT 6 was evaluated 2 h after the intratracheal administration. 15d-PG J2 enhanced the nuclear localization of GATA-3 in the presence of LPS, whereas the nuclear localization of phosphorylated STAT 6 was not altered in the groups. These results suggest that the enhancing effects of 15d-PG J2 on the production of mucin-producing cells might be related, at least in part, to the activation of GATA-3.
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PMID:Effects of 15-deoxy-delta(12,14)-prostaglandin J2 on nuclear localization of GATA-3 in the murine lung in the presence of lipopolysaccharide. 1581 89

The effects of linoleic acid (LA), alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA) were compared to that of palmitic acid (PA), on inflammatory responses in human monocytic THP-1 cells. When cells were pre-incubated with fatty acids for 2-h and then stimulated with lipopolysaccharide for 24-h in the presence of fatty acids, secretion of interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha (TNFalpha) was significantly decreased after treatment with LA, ALA, and DHA versus PA (P < 0.01 for all); ALA and DHA elicited more favorable effects. These effects were comparable to those for 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and were dose-dependent. In addition, LA, ALA, and DHA decreased IL-6, IL-1beta, and TNFalpha gene expression (P < 0.05 for all) and nuclear factor (NF)-kappaB DNA-binding activity, whereas peroxisome proliferator-activated receptor-gamma (PPARgamma) DNA-binding activity was increased. The results indicate that the anti-inflammatory effects of polyunsaturated fatty acids may be, in part, due to the inhibition of NF-kappaB activation via activation of PPARgamma.
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PMID:Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. 1616 25

Retinoic acid-inducible gene-I (RIG-I) is a member of the DExH box protein family and designated as a putative RNA helicase. RIG-I is implicated in host defense and inflammatory reactions by regulating the expression of various genes. RIG-I is expressed in endothelial cells and upregulated with lipopolysaccharide (LPS). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear hormone receptor and regulates gene expressions in response to its specific ligands. In the present study, we examined the effect of PPAR-gamma ligands on the LPS-induced RIG-I expression in cultured human umbilical vein endothelial cells (HUVEC). 15-Deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), a metabolite of PGD2, is a natural ligand for PPAR-gamma and known to modulate inflammatory reactions by regulating the expression of various genes in PPAR-gamma-dependent and -independent manners. LPS-induced RIG-I expression in HUVEC was inhibited by pretreatment of the cells with 15d-PGJ2 in time-and concentration-dependent manners. However, ciglitazone and bisphenol A diglycide ether, authentic and specific ligands for PPAR-gamma, did not affect the RIG-I expression. These results suggest that 15d-PGJ2 inhibits LPS-induced RIG-I expression through a mechanism independent on PPAR-gamma. 15d-PGJ2 may regulate inflammatory reactions, at least in part, by inhibiting the expression of RIG-I.
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PMID:Effect of peroxisome proliferator-activated receptor-gamma ligands on the expression of retinoic acid-inducible gene-I in endothelial cells stimulated with lipopolysaccharide. 1630 4

Peroxisome proliferator-activated receptor-gamma (PPARgamma) and liver X receptor-alpha (LXRalpha) are nuclear ligand-activated transcription factors, which regulate lipid metabolism and inflammation. Murine J774.2 macrophages were stimulated with Escherichia coli lipopolysaccharide (concentration, 10 microg/mL) with or without the PPARgamma ligand, 15-deoxy-Delta prostaglandin J2 (15d-PGJ2), or the LXRalpha ligands, 22(R)-hydroxycholesterol and T0901317 (concentration range, 0.01-10 micromol/L), alone or in combination. Nitric oxide (NO) metabolites and tumor necrosis factor alpha production, inducible NO synthase expression, and mitochondrial respiration were measured. When added to the cells as single agents, 15d-PGJ2, 22(R)-hydroxycholesterol, or T0901317 reduced the lipopolysaccharide-induced NO and tumor necrosis factor alpha production and the inducible NO synthase expression, and partially maintained mitochondrial respiration in a concentration-dependent manner. When added to the cells in combination at suboptimal concentrations, 15d-PGJ2 with 22(R)-hydroxycholesterol, or 15d-PGJ2 with T0901317, exerted anti-inflammatory effects similar to much higher concentrations (10,000-fold to 100,000-fold) of each ligand alone. The anti-inflammatory effects of these ligands, alone or in combination, were associated with reduction of nuclear factor-kappaB activation and with enhancement of PPARgamma DNA binding. LXRalpha expression was upregulated in response to 15d-PGJ2 and to the LXRalpha ligands when added alone or in combination. Immunoprecipitation experiments revealed that PPARgamma interacted with LXRalpha. Our data demonstrate that the PPARgamma ligand, 15d-PGJ2, and the LXRalpha ligands, 22(R)-hydroxycholesterol and T0901317, although binding to different nuclear receptors (i.e., PPARgamma and LXRalpha, respectively), affect mediator production through common cell signaling events and exert a synergistic potentiation in a combined treatment at suboptimal concentrations. Thus, our data suggest that PPARgamma and LXRalpha may interact in controlling the inflammatory response in macrophages.
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PMID:Synergistic effect of peroxisome proliferator activated receptor-gamma and liver X receptor-alpha in the regulation of inflammation in macrophages. 1687 22


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