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)

Haemorrhagic shock leads to decreased proinflammatory cytokine response which is associated with an increased susceptibility to bacterial infections. In the present study, the effect of GM-CSF on lipopolysaccharide (LPS)-induced TNF-alpha release and MAPkinase activation was analysed on the background of a possible immunostimulating activity of this substance. Male BALB/c mice were bled to a mean arterial blood pressure of 50 mmHg for 45 min followed by resuscitation. Peritoneal macrophages were isolated 20 h after haemorrhage and incubated with 10 ng/ml GM-CSF for 6h before LPS stimulation. TNF-alpha synthesis was studied in the culture supernatants using ELISA. Phosphorylation of ERK, p38MAPK and IkappaBalpha was detected by Western blotting. LPS-induced TNF-alpha production of peritoneal macrophages was significantly decreased 20 h after haemorrhage in comparison to the corresponding cells of sham-operated mice. In parallel the phosphorylation of IkappaBalpha was less in LPS-stimulated peritoneal macrophages from haemorrhagic mice. LPS-induced phosphorylation of ERK1/2 was also decreased in peritoneal macrophages isolated after haemorrhagic shock. In contrast, p38MAPK was phosphorylated more intensely after LPS-stimulation in macrophages collected from shocked mice. GM-CSF incubation elevated LPS-induced TNF-alpha response of macrophages from both sham-operated and shocked mice which was accompanied by an elevated IkappaB and ERK phosphorylation. In general, GM-CSF treatment in vitro enhanced peritoneal macrophages LPS-response both in terms of TNF-alpha synthesis and IkappaB and MAPK signalling, but the levels always stayed lower than those of GM-CSF-treated cells from sham-operated animals. In conclusion, GM-CSF preincubation could partly reactivate the depressed functions of peritoneal macrophages and may therefore exert immunostimulating properties after shock or trauma.
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PMID:Haemorrhagic shock in mice--intracellular signalling and immunomodulation of peritoneal macrophages' LPS response. 1701 46

Corticotropin-releasing factor (CRF), the principal regulator of the hypothalamus-pituitary-adrenal (HPA) axis, also modulates the inflammatory response directly, via its effect on mast cells and macrophages. On macrophages, it augments production of lipopolysaccharide (LPS)-induced pro-inflammatory cytokines. CRF and its related peptides may also act as anti-inflammatory agents. Aim of the present work was to examine the role of macrophages on the anti-inflammatory effects of CRF-peptides and the mechanism involved. Thus, we examined if CRF receptor 1 (CRF1) and CRF2 agonists exert any anti-inflammatory effect on primary mouse macrophages. We have found that: (a) CRF, Urocortin (UCN)1 and UCN2 transiently suppressed the release of Tumor Necrosis Factor-alpha (TNF-alpha) in LPS-activated macrophages, an effect peaking at 4 h. This effect did not involve changes on TNF-alpha transcription. (b) CRF peptide-induced suppression of TNF-alpha release depended on induction of COX-2 and PGE2 synthesis. (c) Use of specific CRF1 and CRF2 antagonists suggested that this effect involved both CRF receptor types. (d) The effect of CRF-peptides on COX-2 was mediated via PI3K and p38MAPK. (e) Longer exposure of macrophages to CRF-peptides resulted in induction of TNF-alpha production via enhancement of its transcription. In conclusion, this is the first report suggesting that CRF1 and CRF2 agonists exert a biphasic effect on macrophages. During the early stages of the inflammatory response, they suppress TNF-alpha release via induction of COX-2/PGE2 while later on they induce TNF-alpha transcription. Hence, the reported anti-inflammatory effect of CRF-peptides appears to involve macrophages and is confined at the early stage of inflammation.
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PMID:Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2. 1711 78

Focusing on the final step of osteoclastogenesis, we studied cell fusion from tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells into multinuclear cells. TRAP-positive mononuclear cells before generation of multinuclear cells by cell fusion were differentiated from RAW264.7 cells by treatment with receptor activator of nuclear factor kappa B ligand (RANKL), and then the cells were treated with lipopolysaccharide (LPS), followed by culturing for further 12 h. LPS-induced cell fusion even in the absence of RANKL. Similarly, tumor necrosis factor (TNF)-alpha and peptidoglycan (PGN) induced cell fusion, but M-CSF did not. The cell fusion induced by RANKL, TNF-alpha, and LPS was specifically blocked by osteoprotegerin (OPG), anti-TNF-alpha antibody, and polymyxin B, respectively. LPS- and PGN-induced cell fusion was partly inhibited by anti-TNF-alpha antibody but not by OPG. When TRAP-positive mononuclear cells fused to yield multinuclear cells, phosphorylation of Akt, Src, extracellular signal-regulated kinase (ERK), p38MAPK (p38), and c-Jun NH2-terminal kinase (JNK) was observed. The specific chemical inhibitors LY294002 (PI3K), PP2 (Src), U0126 (MAPK-ERK kinase (MEK)/ERK), and SP600125 (JNK) effectively suppressed cell fusion, although SB203580 (p38) did not. mRNA of nuclear factor of activated T-cells c1 (NFATc1) and dendritic cell-specific transmembrane protein (DC-STAMP) during the cell fusion was quantified, however, there was no obvious difference among the TRAP-positive mononuclear cells treated with or without M-CSF, RANKL, TNF-alpha, LPS, or PGN. Collectively, RANKL, TNF-alpha, LPS, and PGN induced cell fusion of osteoclasts through their own receptors. Subsequent activation of signaling pathways involving PI3K, Src, ERK, and JNK molecules was required for the cell fusion. Although DC-STAMP is considered to be a requisite for cell fusion of osteoclasts, cell fusion-inducing factors other than DC-STAMP might be necessary for the cell fusion.
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PMID:Molecular analysis of RANKL-independent cell fusion of osteoclast-like cells induced by TNF-alpha, lipopolysaccharide, or peptidoglycan. 1717 44

Tumors actively develop different mechanisms such as immunosuppressive cytokine production to escape from immune control and limit the success of immunotherapy. More and more evidences suggest that chronic inflammation contributes to cancer development and progression. Recently, Toll-like receptors (TLRs), the receptors by which immune cells recognize microbial conserved components such as lipopolysaccharide (LPS) then initiate immune and inflammatory responses, have been found to be expressed by some kinds of tumor cells. However, what is the biological function of TLRs on tumor cells and whether human lung cancer cells can express TLRs remain to be fully understood. In the present study, we demonstrate that TLR4 is expressed on human lung cancer cell lines. TLR4 ligation promotes production of immunosuppressive cytokines TGF-beta, VEGF, proangiogenic chemokine IL-8 by human lung cancer cells. In addition, TLR4 ligation induces resistance of human lung cancer cells to TNF-alpha or TRAIL-induced apoptosis. Furthermore, we show p38MAPK activation is necessary for increased VEGF and IL-8 secretion, NF-kappaB activation contributes to apoptosis resistance of human lung cancer cells induced by LPS. Therefore, we demonstrate that TLR4 expressed on human lung cancer cells is functionally active, and may play important roles in promoting immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance.
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PMID:TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. 3244 54

Many neuropeptides that are produced by immune cells have been shown to be involved in the pathogenesis of immunological disorders. Nerve growth factor (NGF) and its receptors are found to be widely expressed in the immune system and regulate both innate and adaptive immune responses. However, the underlying mechanisms by which NGF contributes to pathogenesis of inflammatory diseases remain to be fully understood. Dendritic cells (DCs) are potent initiator for inflammatory and immune responses upon recognization and activation of Toll-like receptors (TLRs). In this study, we demonstrated that stimulation with TLR ligand lipopolysaccharide (LPS), but not lipoteichoic acid (LTA), Poly (I:C) and CpG oligodeoxynucleotide (ODN), could significantly induce expression of NGF and NGF receptor p75(NTR) on mouse bone marrow-derived DCs (BMDCs) in vitro in dose- and time-dependent manners. The expression of NGF and NGF receptor p75(NTR) also increased on splenic DCs isolated from the mice injected with LPS in vivo. However, there was no such effect on DCs derived from TLR4-deficient mice, indicating the LPS-induced upregulation of NGF and p75(NTR) was TLR4 pathway-dependent. Furthermore, LPS-induced upregulation of NGF and p75(NTR) could be inhibited by p38MAPK inhibitor SB203580 and NF-kappaB inhibitor PDTC, suggesting TLR4-triggered activation of p38MAPK and NF-kappaB pathways are responsible for the process. Interestingly, NGF could markedly promote LPS-pretreated BMDCs to secret IL-12p40 and TNF-alpha, which could be abolished by pretreatment with p75(NTR) antagonist or the specific small interference RNA duplex targeting p75(NTR) (p75-siRNA), suggesting the inducible p75(NTR) is critical for the TLR4-initiated inflammatory effect of NGF on BMDCs. Thus, TLR4 signaling can induce expression of NGF and p75 (NTR) on DCs via activation of p38 MAPK and NF-kappaB pathways, suggesting that NGF may be involved in the pathogenesis of inflammatory diseases.
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PMID:TLR4 signaling induces functional nerve growth factor receptor p75NTR on mouse dendritic cells via p38MAPK and NF-kappa B pathways. 1800 62

The pathogenesis of acute lung injury/acute respiratory distress syndrome (ARDS) is complex and involves multiple signal transduction processes. It is believed that p38MAPK (mitogen-activated protein kinase) is one of the most kinases in inflammatory signaling. At present study, we demonstrated the role of p38MAPK in lipopolysaccharide (LPS)-induced acute lung injury with pharmacologic p38MAPK inhibition by SB203580. SB203580, p38MAPK specific inhibitor, was injected (10 mg/kg, i.v.) 30 min before LPS administration (5 mg/kg, i.v.). The hematoxylin-eosin staining of lung tissues showed that p38MAPK inhibition significantly attenuated the pulmonary inflammatory responses induced by LPS. Moreover, SB203580 can also inhibit the inflammatory cytokine release, and reduce the mortality rate of LPS-induced acute lung injury. Further, western blot analysis that showed SB203580 administration can inhibit the activation of NF-kappaB, which was associated with the inhibition of IkappaBalpha degradation in cytoplasm. These data suggest that p38MAPK signaling may be involved in the activation of NF-kappaB, and activation of p38MAPK signaling may be one of the mechanisms of acute lung injury.
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PMID:p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. 1832 78

Heat shock protein 90 (hsp90) inhibitors inactivate and/or degrade various client proteins, including many involved in inflammation. Increased vascular permeability is a hallmark of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Thus, we tested the hypothesis that hsp90 inhibitors may prevent and/or restore endothelial cell (EC) permeability after injury. Exposure of confluent bovine pulmonary arterial endothelial cell (BPAEC) monolayer to TGF-beta1, thrombin, bacterial lipopolysaccharide (LPS), or vascular endothelial growth factor (VEGF) increased BPAEC permeability, as revealed by decreased transendothelial electrical resistance (TER). Treatment of injured endothelium with hsp90 inhibitors completely restored TER of BPAEC. Similarly, preincubation of BPAEC with hsp90 inhibitors prevented the decline in TER induced by the exposure to thrombin, LPS, VEGF, or TGF-beta1. In addition, hsp90 inhibitors restored the EC barrier function after PMA or nocodazole-induced hyperpermeability. These effects of the hsp90 inhibitors were associated with the restoration of TGF-beta1- or nocodazole-induced decrease in VE-cadherin and beta-catenin expression at EC junctions. The protective effect of hsp90 inhibitors on TGF-beta1-induced hyperpermeability was critically dependent upon preservation of F-actin cytoskeleton and was associated with the inhibition of agonist-induced myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, F-actin stress fibers formation, microtubule disassembly, increase in hsp27 phosphorylation, and association of hsp90 with hsp27, but independent of p38MAPK activity. We conclude that hsp90 inhibitors exert barrier protective effects on BPAEC, at least in part, via inhibition of hsp27-mediated, agonist-induced cytoskeletal rearrangement, and therefore may have useful therapeutic value in ALI, ARDS, and other pulmonary inflammatory disease.
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PMID:Heat shock protein 90 inhibitors protect and restore pulmonary endothelial barrier function. 1847 72

Activated microglia participate in neuroinflammation which contributes to neuronal damage in neurodegenerative diseases. Inhibition of microglial activation may have potential anti-inflammatory effects. Our laboratory has previously reported that triptolide, a natural biologically active compound extracted from Tripterygium wilfordii, could protect dopaminergic neurons from inflammation-mediated damage. However, the mechanism by which triptolide inhibits inflammation remains unknown. We reported here that inhibition of prostaglandin E(2) (PGE(2)) production could be a potential mechanism of triptolide to suppress inflammation. Triptolide suppressed c-jun NH2-terminal kinase (JNK) phosphorylation, cyclooxygenase 2 (COX-2) expression and PGE(2) production in microglial cultures treated with lipopolysaccharide (LPS). Triptolide also greatly inhibited the transcriptional activity, but not the DNA-binding activity of nuclear factor-kappaB (NF-kappaB) in microglia following LPS stimulation. These results indicate that triptolide might suppress NF-kappaB activity to down-regulate COX-2 expression. The LPS-stimulated transcriptional activity of NF-kappaB was suppressed by inhibition of p38MAPK, but not by that of JNK and extracellular signal-regulated kinase. Furthermore, the LPS-induced PGE(2) production was reduced by inhibiting these kinases. Taken together, these results suggest that triptolide may suppress neuroinflammation via a mechanism that involves inactivation of two parallel signaling pathways: p38-NF-kappaB-COX-2-PGE(2) and JNK-PGE(2).
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PMID:Triptolide inhibits COX-2 expression and PGE2 release by suppressing the activity of NF-kappaB and JNK in LPS-treated microglia. 1876 8

The Toll-like receptors (TLRs) play an important role in the recognition of Candida albicans components and activation of innate immunity. Phospholipomannan (PLM), a glycolipid, is expressed at the surface of C. albicans cell wall, which acts as a member of the pathogen-associated molecular patterns family. In this study, we sought to clarify whether C. albicans-native PLM could induce an inflammation response in human keratinocytes and to determine the underlying mechanisms. Exposure of cultured human primary keratinocytes to PLM led to the increased gene expression and secretion of proinflammatory cytokines (IL-6) and chemokines (IL-8). PLM hydrolysed with beta-d-mannoside mannohydrolase failed to induce gene expression and secretion of IL-6 and IL-8. PLM up-regulated the mRNA and protein levels of TLR2, whereas the mRNA level of TLR4 was not altered. Keratinocytes challenged with PLM resulted in the activation of NF-kappaB and mitogen-activated protein kinase (MAPKs) including p38. Anti-TLR2 neutralizing antibody, NFkappaB and p38MAPK inhibitors blocked the PLM-induced secretion of IL-6, IL-8 in keratinocytes, but no such effect was observed in pretreatment with anti-TLR4-neutralizing antibody and lipopolysaccharide inhibitor (polymyxin B). These data suggest C. albicans-native PLM may contribute to the inflammatory responses of cutaneous candidiasis in the TLR2-NF-kappaB and p38MAPK signalling pathway dependent manner.
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PMID:Candida albicans phospholipomannan triggers inflammatory responses of human keratinocytes through Toll-like receptor 2. 1919 44

Dendritic cell (DC) maturation, a crucial stage in the immune response, can be induced by various stimuli, such as lipopolysaccharide (LPS). Maturation signals trigger up-regulation of costimulatory molecule expression, increasing the ability of DCs to prime T helper cells. We and others have previously reported that mycophenolic acid (MPA) inhibits DC maturation and activation. However, the mechanisms remain unknown. The primary effect of MPA is inhibition of inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the de novo synthesis of guanosine nucleotide. The process of DC maturation is highly dependent on mitogen-activated protein kinase (MAPK) phosphorylation, especially p38MAPK. We therefore decided to study whether MPA affects these processes. Human monocyte-derived DCs were activated by LPS in the presence or absence of MPA. To assess whether the depletion of guanine affected p38MAPK phosphorylation, increasing doses of exogenous guanosine were added before stimulation. The results by flow cytometry showed that MPA inhibited p38MAPK phosphorylation by 25%. Interestingly, exogenous guanosine did not reverse the MPA inhibition. Our results suggested that MPA inhibits p38MAPK activity independent of IMPDH in human DCs. This effect of MPA may explain its capacity to inhibit maturation marker expression on DCs.
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PMID:Mycophenolic Acid Inhibits p38 Mitogen-Activated Protein Kinase in Human Monocyte-Derived Dendritic Cells Stimulated by Lipopolysaccharide. 1932 59

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