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)

Mechanisms leading to down-regulation of activated microglia and astrocytes are poorly understood, in spite of the potentially detrimental role of activated glia in neurodegeneration. Prostaglandins, produced both by neurons and glia, may serve as mediators of glial and neuronal functions. We examined the influence of cyclopentenone prostaglandins and their precursors on activated glia. As models of glial activation, production of inducible nitric-oxide synthase (iNOS) was studied in lipopolysaccharide-stimulated rat microglia, a murine microglial cell line BV-2, and IL-1beta-stimulated rat astrocytes. Cyclopentenone prostaglandins were potent inhibitors of iNOS induction and were more effective than their precursors, prostaglandins E2 and D2. 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) was the most potent prostaglandin among those tested. In activated microglia, 15d-PGJ2 suppressed iNOS promoter activity, iNOS mRNA, and protein levels. The action of 15d-PGJ2 does not appear to involve its nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) because troglitazone, a specific ligand of PPARgamma, was unable to inhibit iNOS induction, and neither troglitazone nor 15d-PGJ2 could stimulate the activity of a PPAR-dependent promoter in the absence of cotransfected PPARgamma. 15d-PGJ2 did not block nuclear translocation or DNA-binding activity of the transcription factor NFkappaB, but it did inhibit the activity of an NFkappaB reporter construct, suggesting that the mechanism of suppression of microglial iNOS by 15d-PGJ2 may involve interference with NFkappaB transcriptional activity in the nucleus. Thus, our data suggest the existence of a novel pathway mediated by cyclopentenone prostaglandins, which may represent part of a feedback mechanism leading to the cessation of inflammatory glial responses in the brain.
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PMID:Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2. 1020 Mar 20

An early event in acute and chronic inflammation and associated diseases such as atherosclerosis and rheumatoid arthritis is the induced expression of specific adhesion molecules on the surface of endothelial cells (ECs), which subsequently bind leukocytes. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily of transcription factors, are activated by fatty acid metabolites, peroxisome proliferators, and thiazolidinediones and are now recognized as important mediators in the inflammatory response. Whether PPAR activators influence the inflammatory responses of ECs is unknown. We show that the PPAR activators 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), Wyeth 14643, ciglitazone, and troglitazone, but not BRL 49653, partially inhibit the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by ELISA, and monocyte binding to human aortic endothelial cells (HAECs) activated by phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide. The "natural" PPAR activator 15d-PGJ(2) had the greatest potency and was the only tested molecule capable of partially inhibiting the induced expression of E-selectin and neutrophil-like HL60 cell binding to PMA-activated HAECs. Intracellular adhesion molecule-1 induction by PMA was unaffected by any of the molecules tested. Both PPAR-alpha and PPAR-gamma mRNAs were detected in HAECs by using reverse transcription-polymerase chain reaction and a ribonuclease protection assay; however, we have yet to determine which, if any, of the PPARs are mediating this process. These results suggest that certain PPAR activators may help limit chronic inflammation mediated by VCAM-1 and monocytes without affecting acute inflammation mediated by E-selectin and neutrophil binding.
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PMID:Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. 1047 50

Peroxisome proliferator-activated receptor gamma (PPARgamma), a primary regulator of adipocyte differentiation, has been implicated in the regulation of monocyte and macrophage function in vitro. We report that PPARgamma protein is expressed in porcine peripheral white blood cells (WBC), and that PPARgamma1 but not gamma2 mRNA predominates. Additionally, we provide the first evidence that in vivo lipopolysaccharide challenge (LPS, 25 microg/kg BW) causes a dynamic increase in PPARgamma protein expression in peripheral WBC (P < 0.05). PPARgamma expression was increased 2-fold over basal (1 hr post-LPS), was maximal by 4 hr (3-fold), and was normalized to control by 8 hr post-LPS. Changes in PPARgamma expression coincided with or closely followed LPS-induced changes in plasma cortisol, TNF-alpha, insulin, IGF-1, glucose, and free fatty acids. These data suggest that induction of PPARgamma expression in WBC may play a role in host response to acute inflammatory challenge and may prove to be an important target of anti-inflammatory therapies.
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PMID:Peroxisome proliferator-activated receptor gamma1 expression in porcine white blood cells: dynamic regulation with acute endotoxemia. 1051 51

B/macrophage cells are biphenotypic leukocytes of unknown function that simultaneously express B lymphocyte (IgM, IgD, B220, CD5) and macrophage (phagocytosis, F4/80, Mac-1) characteristics. B/macrophage cells can be generated from purified mouse B lymphocytes incubated in fibroblast-conditioned medium. A potential role for B/macrophage cells in inflammation was shown by their ability to express prostaglandin H synthase-1 (COX-1) and prostaglandin H synthase-2 (COX-2) and by their production of prostaglandin (PG) E(2). COX-1 and COX-2 mRNA expression is not observed in the precursor B lymphocytes and is not known to be a property of B lineage cells. In contrast, COX-2 and the prostanoids PGE(2), PGF(2alpha) and PGD(2) are highly inducible in B/ macrophage cells upon stimulation with lipopolysaccharide, CD40 ligand, or via engagement of surface IgM, supporting a role for these cells in inflammation. PGD(2) and its metabolites are of interest because they activate the nuclear receptor PPARgamma that regulates lipid metabolism. The B/macrophage represents the first instance of a normal B-lineage cell capable of expressing COX-2. Importantly, B/macrophage cells were identified in vivo, providing evidence that they may play a significant role in immune responses. Since PGE(2) blunts IL-12 production, its synthesis by B/macrophage cells may shift the balance of an immune response towards Th2 and humoral immunity.
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PMID:Biphenotypic B/macrophage cells express COX-1 and up-regulate COX-2 expression and prostaglandin E(2) production in response to pro-inflammatory signals. 1055 36

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily that activates target gene transcription in a ligand-dependent manner. In addition, liganded PPARgamma can inhibit transcription of genes induced by gamma interferon (IFN-gamma) and/or lipopolysaccharides (LPSs), including the inducible nitric oxide synthase (iNOS) gene. Inhibition of the iNOS promoter is achieved partially through antagonizing the activities of NF-kappaB, AP-1, and STAT1, which are known to mediate effects of LPS and IFN-gamma. Previous studies have suggested that transrepression of these factors by nuclear receptors involves competition for limiting amounts of the general coactivators CREB-binding protein (CBP) and p300. CBP and p300 are thought to be recruited to nuclear receptors through bridging factors that include SRC-1, although CBP also interacts directly with PPARgamma through its amino terminus. These observations have raised questions concerning the involvement of SRC-1-like factors in CBP recruitment and transrepression. We here provide evidence that PPARgamma's ability to repress iNOS transcription requires the ligand-dependent charge clamp that mediates interactions with CBP and SRC-1. Single amino acid mutations in PPARgamma that abolished ligand-dependent interactions with SRC-1 and CBP not only resulted in complete loss of transactivation activity but also abolished transrepression. Conversely, a CBP deletion mutant containing the SRC-1 interaction domain but lacking the N-terminal PPARgamma interaction domain was inactive as a PPARgamma coactivator and failed to rescue transrepression. Together, these findings are consistent with a model in which transrepression by PPARgamma is achieved by targeting CBP through direct interaction with its N-terminal domain and via SRC-1-like bridge factors.
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PMID:Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. 1084 96

The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor alpha (TNFalpha)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFalpha- or LPS-induced NFkappaB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFkappaB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFkappaB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2), also induces COX-2 expression and inhibits TNFalpha-induced NFkappaB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Delta(12,14)-prostaglandin J(2) also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1alpha in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.
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PMID:Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways. 1086 99

In this study, the anti-inflammatory actions of the peroxisome proliferator-activated receptor (PPAR)-gamma agonists 15-deoxy-delta 12,14-prostaglandin J2 (15-d-delta 12,14-PGJ2) and troglitazone have been examined. Treatment of RAW 264.7 cells and CD-1 mouse peritoneal macrophages with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) results in inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX-2) and interleukin-1 (IL-1) expression, increased production of nitric oxide, and the release of IL-1. In a concentration-dependent manner, 15-d-delta 12,14-PGJ2 inhibits each of these proinflammatory actions of LPS + IFN-gamma, with half-maximal inhibition at approximately 0.5 microg/ml and complete inhibition at 1-5 microg/ml. The inhibitory actions of 15-d-delta 12,14-PGJ2 on LPS + IFN-gamma-induced inflammatory events are not associated with the inhibition of iNOS enzymatic activity or macrophage cell death, but appear to result from an inhibition of iNOS and IL-1 transcription. In addition, the anti-inflammatory actions of 15-d-delta 12,14-PGJ2 are not limited to peritoneal macrophages, as 15-d-delta 12,14-PGJ2 prevents TNF-alpha + LPS-induced resident islet macrophage expression of IL-1beta and beta-cell expression of iNOS stimulated by the local release of IL-1 in rat islets. 15-d-delta 12,14-PGJ2 appears to be approximately 10-fold more effective at inhibiting resident islet macrophage activation (in response to TNF + LPS) than IL-1-induced nitrite production by beta-cells. Two mechanisms appear to be associated with the antiinflammatory actions of both 15-d-delta 12,14-PGJ2 and troglitazone: 1) the direct inhibition of cytokine- and endotoxin-stimulated iNOS and IL-1 transcription; and 2) the inhibition of IL-1 signaling, an event associated with PPAR-gamma agonist-induced activation of the heat shock response (as assayed by heat shock protein 70 expression). These findings indicate that the PPAR-gamma agonists, troglitazone and the J series of prostaglandins, are potent anti-inflammatory agents that prevent cytokine- and endotoxin-stimulated activation of peripheral and resident tissue macrophages and cytokine-induced iNOS expression by beta-cells by the inhibition of transcriptional activation and induction of the heat shock response.
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PMID:Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone: evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. 1086 55

Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid 15-deoxy-Delta(12,14) prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPARgamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPARgamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. 1099 30

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Recently, PPAR activators have been shown to inhibit the production of proinflammatory cytokines in macrophages or vascular smooth muscle cells. It has been reported that tumor necrosis factor-alpha (TNF-alpha) expression is elevated in the failing heart and that TNF-alpha has a negative inotropic effect on cardiac myocytes. Therefore, we examined the effects of PPARalpha and PPARgamma activators on expression of TNF-alpha in neonatal rat cardiac myocytes. Northern blot analysis revealed expression of PPARalpha and PPARgamma mRNA in cardiac myocytes. Immunofluorescent staining demonstrated that both PPARalpha and PPARgamma were expressed in the nuclei of cells. When cardiac myocytes were transfected with PPAR responsive element (PPRE)-luciferase reporter plasmid, both PPARalpha and PPARgamma activators increased the promoter activity. Cardiomyocytes were stimulated with lipopolysaccharide (LPS), and the levels of TNF-alpha in the medium were measured by ELISA. After exposure to LPS, the levels of TNF-alpha significantly increased. However, pretreatment of myocytes with PPARalpha or PPARgamma activators decreased LPS-induced expression of TNF-alpha in the medium. Both PPARalpha and PPARgamma activators also inhibited LPS-induced increase in TNF-alpha mRNA in myocytes. In addition, electrophoretic mobility shift assays demonstrated that PPAR activators reduced LPS-induced nuclear factor-kappaB activation. These results suggest that both PPARalpha and PPARgamma activators inhibit cardiac expression of TNF-alpha in part by antagonizing nuclear factor-kappaB activity and that treatment with PPAR activators may lead to improvement in congestive heart failure.
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PMID:Peroxisome proliferator-activated receptor activators inhibit lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal rat cardiac myocytes. 1100 65

15-Deoxy-Delta(12,14)-prostaglandin J(2) (dPGJ(2)) is a metabolite of prostaglandin D(2), that binds to peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma and prostaglandin D(2) synthase, which is required for dPGJ(2) synthesis, are predominantly expressed in macrophages. In contrast, IL-10 and IL-12 produced by macrophages stimulate Th1 and Th2 immune response, respectively. This study investigated the effect of dPGJ(2) on IL-10 and IL-12 production by macrophages in response to lipopolysaccharide (LPS). Our data clearly demonstrated that dPGJ(2) inhibits LPS-induced IL-10 and IL-12 production by macrophages. A different agonist of PPARgamma, 13-hydroxyoctadecadienoic acid, similarly inhibited the production of IL-10 and IL-12 in response to LPS. Further, dPGJ(2) did not appear to act through the PGD(2) receptor. These results suggest that dPGJ(2) may inhibit LPS-induced IL-10 and IL-12 production by macrophages through PPARgamma.
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PMID:15-Deoxy-delta(12,14)-prostaglandin J(2) inhibits IL-10 and IL-12 production by macrophages. 1132 5

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