Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tyrosine phosphorylation is an early step in lipopolysaccharide (LPS) stimulated monocytes and macrophages that appears to play a key role in signal transduction. We have demonstrated that LPS purified from Actinobacillus actinomycetemcomitans also increases protein tyrosine phosphorylation in human gingival fibroblasts (HGF). This effect was elicited rapidly after LPS stimulation at concentrations that stimulate anti-bacterial responses in human gingival fibroblasts. Two main proteins, with an apparent molecular weight of 44 and 42 kDa, were phosphorylated after LPS stimulation of the human gingival fibroblasts. The phosphorylation was detected after 5 to 15 min and reached the maximum at 30 min of treatment. The increase in tyrosine phosphorylation was apparent following stimulation with LPS at 10 ng/ml and the response was dose dependent up to 10 microg/ml. Pretreatment with the tyrosine kinase inhibitors, herbimycin A and genistein inhibited the LPS-stimulated phosphorylation of p44 and p42 MAP kinases in a dose dependent manner. Pretreatment of human gingival fibroblasts with antibodies anti-CD14 or anti-TLR-4 but not anti-TLR-2 inhibited the LPS-induced tyrosine phosphorylation of p44 and p42. Additionally, LPS-induced p44 and p42 phosphorylation was inhibited by polymyxin treatment. These findings demonstrate that LPS from A. actinomycetemcomintans increases rapidly p44 and p42 phosphorylation (ERK 1 and ERK 2, respectively) in human gingival fibroblasts. Our data also suggest that CD14 and TLR-4 receptors are involved in the LPS effects in human gingival fibroblasts.
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PMID:Actinobacillus actinomycetemcomitans lipopolysaccharide stimulates the phosphorylation of p44 and p42 MAP kinases through CD14 and TLR-4 receptor activation in human gingival fibroblasts. 1631 59

After engulfment of apoptotic cells through phosphatidylserine (PS)-mediated recognition, microglia secrete prostaglandin E2 (PGE2), a potent anti-inflammatory molecule in the central nervous system. Despite the clinical significance, the mechanism underlying PGE2 production by phagocytosis of apoptotic cells is poorly understood. In the present study, we used PS liposomes to elucidate the phagocytic pathway for PGE2 production in microglia, because PS liposomes mimic the effects of apoptotic cells on microglia/macrophages. The level of PGE2 in the culture medium of primary cultured rat microglia was significantly increased by PS liposomes treatment but not by phosphatidylcholine liposomes treatment. The specific ligand for class B scavenger receptor (SR-B), high density lipoprotein, significantly suppressed PS liposome-induced PGE2 production. PS liposomes were immediately phagocytosed by microglia and sorted to endosomes/lysosomes. Cyclooxygenase (COX)-2 and membrane-bound prostaglandin E synthase-1 (mPGES-1) were induced by treatment with lipopolysaccharide (LPS) but not with PS liposomes. On the other hand, mPGES-2 and cytosolic PGES (cPGES) that are functionally coupled with COX-1 were upregulated after treatment with PS liposomes or LPS. Furthermore, PS liposome-induced PGE2 production was significantly suppressed by indomethacin, a preferential COX-1 inhibitor, but not by NS-398, a selective COX-2 inhibitor. PS liposomes induced activation of p44/p42 extracellular signal-regulated kinase (ERK) but not p38 mitogen-activated protein kinase in SR-BI independent manner. These observations strongly suggest that the up-regulation of terminal PGESs that are preferentially coupled with COX-1, especially mPGES-2, plays the pivotal role in PS liposome-induced PGE2 production by microglia. Although SR-BI plays an essential role in PS liposome-induced PGE2 production, other PS-recognizing receptors, possibly PS-specific receptor, could also promote PGE2 production by transducing intracellular signals including p44/p42 ERK after PS liposomes treatment.
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PMID:Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia. 1637 Dec 34

We report that the synthetic chalcone 2',4',6'-tris(methoxymethoxy) chalcone (TMMC) is an anti-inflammatory compound that reduces nitric oxide (NO) production by inhibiting of inducible NO synthase (iNOS) expression, and that TMMC decreases the degradation of the inhibitory factor kappaB, leading to inhibition of nuclear factor-kappaB translocation into the nucleus in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. We also demonstrate that TMMC by itself is a potent inducer of heme oxygenase 1 (HO-1). Inhibition of HO-1 activity or scavenging of carbon monoxide, a byproduct of heme degradation, significantly attenuated this anti-inflammatory action. Treating cells with the specific p42/44 MAPK inhibitor, PD98059, blocked the TMMC-mediated induction of HO-1 and the inhibition of LPS-stimulated expression of iNOS. TMMC also depleted intracellular GSH. Our data suggest that TMMC exerts an anti-inflammatory effect in macrophages through a mechanism that involves the induction of HO-1, which is mediated by activation of p42/44 MAPK and GSH depletion.
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PMID:Heme oxygenase 1 mediates anti-inflammatory effects of 2',4',6'-tris(methoxymethoxy) chalcone. 1648 Sep 75

Although lead and lipopolysaccharide (LPS), both important environmental pollutants, activate cells through different receptors and participate in distinct upstream signaling pathways, Pb increases the amount of LPS-induced tumor necrosis factor-alpha (TNF-alpha). We examined the cells responsible for the excess production of Pb-increased LPS-induced TNF-alpha and liver injury, and the roles of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) in the induction of TNF-alpha. Peritoneal injection of Pb alone (100 micromol/kg) or a low dose of LPS (5 mg/kg) did not affect serum TNF-alpha or liver functions in A/J mice. In contrast, coexposure to these noneffective doses of Pb plus LPS (Pb+LPS) strongly induced TNF-alpha expression and resulted in profound liver injury. Direct inhibition of TNF-alpha or functional inactivation of monocytes/macrophages significantly decreased the level of Pb+LPS-induced serum TNF-alpha and concurrently ameliorated liver injury. Pb+LPS coexposure stimulated the phosphorylation of p42/44 MAPK and the expression of TNF-alpha in CD14+ cells of cultured mouse whole blood, peritoneal macrophages, and RAW264.7 cells. Moreover, blocking PKC or MAPK effectively reduced Pb+LPS-induced TNF-alpha expression and liver injury. In summary, monocytes/macrophages were the cells primarily responsible for producing, through the PKC/MAPK pathway, the excess Pb-increased/LPS-induced TNF-alpha that caused liver injury. alpha.
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PMID:Lead increases lipopolysaccharide-induced liver-injury through tumor necrosis factor-alpha overexpression by monocytes/macrophages: role of protein kinase C and P42/44 mitogen-activated protein kinase. 1658 37

To determine whether the p44/p42 MAPK (ERK1/2) signaling pathway is involved in the activation of CRH-containing neurons in the hypothalamic paraventricular nucleus (PVN) after bacterial lipopolysaccharide (LPS) administration, Sprague Dawley rats were injected with LPS, and studied after 2, 6, 9, and 12 h. In saline-treated controls, isolated weak phosphorylated (phospho)ERK1/2 immunoreactive neurons were observed in the PVN. However, a dramatic increase in phospho-ERK1/2 immunoreactivity was apparent in the PVN 2 h after LPS administration, and gradually declined to baseline levels 9-12 h after injection. By double-labeling immunofluorescence, all CRH-containing neurons in the PVN contained phospho-ERK1/2 2 h after LPS. Intracerebroventricular administration of the MAPK inhibitor, PD98059, prevented LPS-induced ERK1/2 phosphorylation, c-fos activation, and the increase of CRH gene expression in the PVN but had no effect on c-fos activation in brainstem A2-C1/C2 regions. We conclude that LPS rapidly increases the phospho-ERK1/2 in CRH-containing neurons in the PVN and that activation of MAPKs is necessary for LPS-induced activation of the hypothalamic-pituitary-adrenal axis.
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PMID:Mitogen-activated protein kinase contributes to lipopolysaccharide-induced activation of corticotropin-releasing hormone synthesizing neurons in the hypothalamic paraventricular nucleus. 1818 39

The extract of the root of Acanthopanax chiisanensis Nakai is used for the treatment of inflammation. To analyse the action mechanism of this extract, the effect of hyperin (quercetin-3-O-beta-d-galactose) isolated from the ethyl acetate fraction of the root of A. chiisanensis on nitrite production and induction of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS, 1 microg/mL)-stimulated rat peritoneal macrophages were examined. The effect of the structurally related compounds, isoquercitrin (quercetin-3-O-beta-d-glucose) and quercetin (an aglycone of the two compounds) isolated from the extract of the leaves of Vaccinium koreanum Nakai was also examined to compare the effect. It was shown that hyperin inhibited the LPS-induced iNOS expression and nitrite production. Of the three compounds, quercetin showed the most potent inhibitory activity. The phosphorylation of p44/42 mitogen activated protein kinase (MAPK), p38 MAPK and c-Jun N-terminal kinase (JNK) were also inhibited by these compounds. These findings suggested that hyperin in the extract of the root of A. chiisanensis inhibits nitric oxide (NO) production through inhibition of the expression of iNOS by attenuation of p44/p42 MAPK, p38 MAPK and JNK, and thus participates in the antiinflammatory activity of the extract.
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PMID:Effects of hyperin, isoquercitrin and quercetin on lipopolysaccharide-induced nitrite production in rat peritoneal macrophages. 1881 9

Induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production is thought to have beneficial immunomodulatory effects in acute and chronic inflammatory disorders. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, withaferin A inhibited LPS-induced expression of both iNOS protein and mRNA in a dose-dependent manner. To investigate the mechanism by which withaferin A inhibits iNOS gene expression, we examined activation of mitogen-activated protein kinases (MAPKs) and Akt in Raw 264.7 cells. We did not observe any significant changes in the phosphorylation of p38 MAPK in cells treated with LPS alone or LPS plus withaferin A. However, LPS-induced Akt phosphorylation was markedly inhibited by withaferin A, while the phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs) was slightly inhibited by withaferin A treatment. Withaferin A prevented IkappaB phosphorylation, blocking the subsequent nuclear translocation of nuclear factor-kappaB (NF-kappaB) and inhibiting its DNA binding activity. LPS-induced p65 phosphorylation, which is mediated by extracellular signal-regulated kinase (ERK) and Akt pathways, was attenuated by withaferin A treatment. Moreover, LPS-induced NO production and NF-kappaB activation were inhibited by SH-6, a specific inhibitor of Akt. Taken together, these results suggest that withaferin A inhibits inflammation through inhibition of NO production and iNOS expression, at least in part, by blocking Akt and subsequently down-regulating NF-kappaB activity.
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PMID:Withaferin A inhibits iNOS expression and nitric oxide production by Akt inactivation and down-regulating LPS-induced activity of NF-kappaB in RAW 264.7 cells. 1883 70

Previous investigations have shown the immunosuppressive activity of the immunophilin-binding macrolide Sanglifehrin A (SFA). In adults, SFA also exerts anti-inflammatory properties in lipopolysaccharide (LPS)-stimulated whole blood cultures. It was the aim of this study to investigate whether the unique properties of SFA are also present in the neonatal immune system, as neonates are susceptible to serious infection due to an immaturity of immune responses. We used a whole blood assay to investigate the impact of SFA on T-cell proliferation and secretion of T-cell cytokines upon Anti-CD3/Anti-CD28 costimulation. In addition, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) secretion was assessed in whole blood monocytes after LPS stimulation. Furthermore, the influence of SFA on LPS-induced signal transduction pathways, specifically the activity of p42/44, p38 and Ap-1, was assessed in neonatal PBMCs. Neonatal cord blood lymphocytes were found to have a diminished IL-4, IL-6, TNF-alpha and interferon-gamma (IFN-gamma) production upon Anti-CD3/Anti-CD28 costimulation compared to adult whole blood lymphocytes. In contrast, no significant differences were noted for either IL-2 production or proliferation of CD4+ cells. Upon addition of 1000nM SFA to neonatal whole blood cultures, a significant inhibition of both, T-cell cytokine secretion and proliferation was demonstrated. In line with data from adult whole blood cultures, SFA proved to be a strong inhibitor of LPS-induced expression of IL-6 and TNF-alpha in the neonatal whole blood system. In signal transduction studies of the LPS pathway, a potent inhibition of the protein kinase p42/44 was demonstrated. SFA was also shown to block nuclear translocation of the transcription factor Ap-1. SFA was proved to have inhibitory effects on innate and acquired immune response of neonatal whole blood cells. The protein kinase p42/44 and the transcription factor Ap-1 were demonstrated to be potential key molecules for the anti-inflammatory effect of SFA.
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PMID:Immunomodulatory effects of Sanglifehrin A in the innate and acquired immune response of neonatal whole blood cells. 1921 6

The purpose of this study was to identify the role of phospholipase D2 (PLD2) in lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis. LPS enhanced NO synthesis and inducible nitric oxide synthase (iNOS) expression in macrophage cell line, Raw 264.7 cells. When Raw 264.7 cells were stimulated with LPS, the expressions of PLDs were increased. Thus, to investigate the role of PLD in NO synthesis, we transfected PLD1, PLD2, and their dominant negative forms to Raw 264.7 cells, respectively. Interestingly, only PLD2 overexpression, but not that of PLD1, increased NO synthesis and iNOS expression. Moreover, LPS-induced NO synthesis and iNOS expression were blocked by PLD2 siRNA, suggesting that LPS upregulates NO synthesis through PLD2. Next, we investigated the S6K1-p42/44 MAPK-STAT3 signaling pathway in LPS-induced NO synthesis mechanism. Knockdown of PLD2 with siRNA also decreased phosphorylation of S6K1, p42/44 MAPK and STAT3 induced by LPS. Furthermore, we found that STAT3 bound with the iNOS promoter, and their binding was mediated by PLD2. Taken together, our results demonstrate the importance of PLD2 for LPS-induced NO synthesis in Raw 264.7 cells with involvement of the S6K1-p42/44 MAPK-STAT3 pathway.
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PMID:Phospholipase D2 acts as an important regulator in LPS-induced nitric oxide synthesis in Raw 264.7 cells. 1996 59

The objective of this study was to investigate the effects of glucose-based peritoneal dialysis (PD) fluids and icodextrin-based PD fluids on the expression of Toll-like receptor 2 (TLR2)/TLR4 and subsequent ligand-induced mitogen-activated protein kinase (MAPK) and NF-kappaB signaling and tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA expression in human peritoneal mesothelial cells (HPMCs). A human peritoneal mesothelial cell line (HMrSV5) was stimulated with glucose-based and icodextrin-based peritoneal dialysis fluids. Cell viability was assessed using MTT [3-(4,5-dimethylthiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. TLR2/TLR4 expression was determined by real-time PCR, Western blotting, and an immunofluorescence assay. In addition, cells were pretreated with different PD solutions and then incubated with Pam3CSK4 or lipopolysaccharide (LPS), and the degrees of MAPK and NF-kappaB activation were reflected by detecting the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and p65, using a Western blot method. TNF-alpha and IL-1beta mRNA expression was measured by real-time PCR. Glucose-based peritoneal dialysis fluids suppressed the expression of TLR2 and TLR4 proteins in HPMCs. Challenge of cells with either Pam3CSK4 or LPS resulted in impaired TNF-alpha and IL-1beta production. Moreover, reduced TLR2 and TLR4 levels in glucose-based peritoneal dialysis solution-treated mesothelial cells were accompanied by reduced p42/44 (ERK1/2), JNK, p38 MAPK, and NF-kappaB p65 phosphorylation upon TLR ligand engagement. No significant changes in MAPK and NF-kappaB signaling and TNF-alpha and IL-1beta mRNA expression were observed in icodextrin-based PD solution-treated mesothelial cells. Glucose-based PD solution, but not icodextrin-based PD solution, downregulates expression of TLR2/TLR4 by human peritoneal mesothelial cells and triggers hyporesponsiveness to pathogen-associated molecular patterns.
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PMID:Glucose-based peritoneal dialysis fluids downregulate toll-like receptors and trigger hyporesponsiveness to pathogen-associated molecular patterns in human peritoneal mesothelial cells. 2020 Jan 88


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