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)

This study aimed to investigate the time-course of the effect of beta2-adrenoceptor stimulation with terbutaline on lipopolysaccharide (LPS)-induced tumour necrosis factor(TNF)-alpha production in rat mesangial cells. Cells were cultured from 0-24 h in the presence of LPS (1 microg/ml) and/or terbutaline (10(-7)-10(-8) mol/l). After 1 h of incubation, terbutaline inhibited TNF-alpha protein release as well as transcription and translation of TNF-alpha and mitogen activated protein kinase (MAPK, p42/p44) activity. At 3 h, terbutaline enhanced intracellular cAMP but suppressed TNF-alpha release and transcription. By 24 h, whereas terbutaline was no longer influencing transcription or translation, TNF-alpha release remained depressed which correlated with an increase in supernatant interleukin (IL)-6. Terbutaline did not affect the LPS-induced IL-10 produced in the cell. These findings indicate that beta2-adrenoceptor stimulation during an LPS challenge prevented TNF-alpha production as a consequence of MAPK inhibition and enhanced cAMP generation, which at a later stage was associated with an anti-inflammatory effect of IL-6.
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PMID:Beta2-adrenoceptor agonist suppresses tumour necrosis factor production in rat mesangial cells. 1085 65

CD14-expressing Chinese hamster ovary (CD14-CHO) cells, established by transfection of human CD14 DNA, acquired high responsiveness to lipopolysaccharide (LPS) through membrane-bound CD14 expression. LPS induced DNA synthesis and activated a series of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase 1/2 (Erk1/2), p38, and c-Jun N-terminal kinase/stress-activated protein kinase, in CD14-CHO cells but not in mock-transfected CHO cells. Anti-CD14 antibody completely abrogated both LPS-induced DNA synthesis and LPS-induced phosphorylation of those MAP kinases, suggesting a critical role of membrane-bound CD14 in LPS signaling. A p38 MAP kinase inhibitor, SB203580, markedly augmented LPS-induced DNA synthesis in CD14-CHO cells, whereas an Erk1/2 inhibitor, PD98059, had no affect. On the other hand, SB203580 exhibited no effect on epidermal growth factor-induced DNA synthesis in CD14-CHO cells, although PD98059 inhibited it significantly. The activation and inactivation of p38 MAP kinase with dominant negative and dominant positive mutants also suggested the participation of p38 MAP kinase in LPS-induced DNA synthesis. It was therefore suggested that the activation of p38 MAP kinase can negatively regulate LPS-induced cell proliferation in CD14-CHO cells.
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PMID:Inhibition of p38 mitogen-activated protein kinase augments lipopolysaccharide-induced cell proliferation in CD14-expressing Chinese hamster ovary cells. 1115 88

The effect of caspase inhibitors on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 267.4 murine macrophage cells was investigated. Pretreatment of RAW cells with a broad caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), resulted in a striking reduction in LPS-induced NO production. Z-VAD-FMK inhibited LPS-induced NF-kappaB activation. Furthermore, it blocked phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) but not that of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases. Similarly, a caspase 3-specific inhibitor, Z-Asp-Glu-Val-Asp-fluoromethylketone, inhibited NO production, NF-kappaB activation, and JNK/SAPK phosphorylation in LPS-stimulated RAW cells. The attenuated NO production was due to inhibition of the expression of an inducible-type NO synthase (iNOS). The overexpression of the dominant negative mutant of JNK/SAPK and the addition of a JNK/SAPK inhibitor blocked iNOS expression but did not block LPS-induced caspase 3 activation. It was therefore suggested that the inhibition of caspase 3 might abrogate LPS-induced NO production by preventing the activation of NF-kappaB and JNK/SAPK. The caspase family, especially caspase 3, is likely to play an important role in the signal transduction for iNOS-mediated NO production in LPS-stimulated mouse macrophages.
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PMID:Inhibition of caspase 3 abrogates lipopolysaccharide-induced nitric oxide production by preventing activation of NF-kappaB and c-Jun NH2-terminal kinase/stress-activated protein kinase in RAW 264.7 murine macrophage cells. 1117 93

The induction of dendritic cell (DC) maturation is critical for the induction of Ag-specific T lymphocyte responses and may be essential for the development of human vaccines relying on T cell immunity. In this study, we have investigated the effects of monophosphoryl lipid A (MPL) on human monocyte-derived DC as well as peripheral blood T cells. Calcium mobilization, mitogen-activated protein kinase activation, and the NF-kappaB transcription factor were induced after MPL stimulation of DC and required high doses of MPL (100 microg/ml). Maturation parameters such as production of IL-12 and increases in cell surface expression of HLA-DR, CD80, CD86, CD40, and CD83 were observed following DC treatment with MPL. However, lower levels of IL-12 were induced by MPL when compared with lipopolysaccharide. This is likely to be related to differences in the kinetics of extracellular signal-related kinase 1/2 and p-38 phosphorylation induced by both molecules. Although maturation induced by MPL was weaker when compared with lipopolysaccharide, it appeared to be sufficient to support optimal activation of allogeneic naive CD45RA(+) T cell and anti-tetanus toxoid CD4 T cells. MPL at low doses (5 microg/ml) had no impact on DC maturation, while its addition to DC-T cell cocultures induced full T cell activation. The observed effect was related to the fact that MPL also acts directly on T cells, likely through their Toll-like receptors, by increasing their intracellular calcium and up-regulating their CD40 ligand expression. Together, these data support a model where MPL enhances T cell responses by having an impact on DC and T cells.
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PMID:Monophosphoryl lipid A activates both human dendritic cells and T cells. 1177 91

The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive to lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) by which LPS stimulates cultured hepatocytes remain uncertain. Cultures of primary mouse hepatocytes were incubated with LPS to assess its effects on the global gene expression, hepatic transcription factors, and mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that LPS modulates the selective expression of more than 80 genes and expressed sequence tags. We have shown previously that hepatocytes express CD14, which is required both for uptake and responsiveness to LPS. In other cells, responsiveness to microbial products requires expression of Toll-like receptors (TLR) and their associated accessory molecules. Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules. The MAP kinase extracellular signal-regulated kinase 1/2 was phosphorylated in response to LPS in mouse hepatocytes, and the levels of phosphorylation were lower in hepatocytes from TLR4-null mice. NF-kappa B activation was reduced in TLR4-mutant or -null hepatocytes compared to control hepatocytes, and this defect was partially restored by adenoviral transduction of mouse TLR4. Thus, hepatocytes respond to nanogram concentrations of LPS through a TLR4 response pathway.
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PMID:Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. 1206 83

Periodontal disease is the major cause of adult tooth loss and is commonly characterized by a chronic inflammation caused by infection of oral bacteria. Porphyromonas gingivalis (P. gingivalis) is one of the suspected periodontopathic bacteria and is frequently isolated from the periodontal pockets of patients with chronic periodontal disease. The lipopolysaccharide (LPS) of P. gingivalis is a key factor in the development of periodontitis. Gingival fibroblasts, which are the major constituents of gingival connective tissue, may directly interact with bacteria and bacterial products, including LPS, in periodontitis lesions. It is suggested that gingival fibroblasts play an important role in the host responses to LPS in periodontal disease. P. gingivalis LPS enhances the production of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) in gingival fibroblasts. However, the receptor that binds with P. gingivalis LPS on gingival fibroblasts remained unknown for many years. Recently, it was demonstrated that P. gingivalis LPS binds to gingival fibroblasts. It was also found that gingival fibroblasts express CD14, Toll-like receptor 4 (TLR4), and myeloid differentiation primary response gene 88 (MyD88). P. gingivalis LPS treatment of gingival fibroblasts activates several intracellular proteins, including protein tyrosine kinases, and up-regulates the expression of monocyte chemoattractant protein-1 (MCP-1), extracellular signal-regulated kinase 1 (ERK1), and signal-regulated kinase 2 (ERK2), IL-1 receptor-associated kinase (IRAK), nuclear factor-kappaB (NF-kappaB), and activating protein-1 (AP-1). These results suggest that the binding of P. gingivalis LPS to CD14 and TLR4 on gingival fibroblasts activates various second-messenger systems. In this article, we review recent findings on the signaling pathways induced by the binding of P. gingivalis LPS to CD14 and Toll-like receptors (TLRs) in gingival fibroblasts.
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PMID:Porphyromonas gingivalis lipopolysaccharide signaling in gingival fibroblasts-CD14 and Toll-like receptors. 1209 56

Basic and clinical evidence has provided insight into the molecular events that link inflammation and coagulation. Increased expression of tissue factor (TF) by circulating and vascular cells has been indicated as responsible for the thrombotic complications associated with acute and chronic inflammation. TF is indeed inducible in circulating and vascular cells by cytokines and bacterial lipopolysaccharide (LPS) and its expression triggers the coagulation. The cyclopentenone prostaglandins are naturally occurring prostaglandin D2 (PGD2) derivatives that comprises prostaglandin J2 (PGJ2) and its metabolites delta12-PGJ2 and 15-deoxy- delta12,14-prostaglandin J2 (15d-PGJ2). These compounds, detected in vivo in a later phase of the inflammatory response, are characterized by anti-inflammatory activity and participate to the resolution of inflammation. We have here investigated the effect of 15d-PGJ2 on TF expression in human macrophages and endothelial cells (HUVEC). Our results indicate that 15d-PGJ2 down-regulates LPS- and TNFalpha-induced TF activity, protein and mRNA through inhibition of TF gene transcription. The effect of 15d-PGJ2 is targeted to the NF-kappaB/I-kappaB pathway and to the mitogen activated protein kinase ERK1/2. A role of PPAR-gamma activation in TF inhibition by 15d-PGJ2 was excluded. We conclude that 15d-PGJ2 negatively affects TF expression in macrophages and endothelial cells through a PPARgamma-independent mechanism. This down-regulation may be crucial to limit excessive blood clotting activation in immuno-inflammatory diseases.
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PMID:15-deoxy-delta12,14-Prostaglandin J2 inhibits tissue factor expression in human macrophages and endothelial cells: evidence for ERK1/2 signaling pathway blockade. 1235 85

In the present study, we investigated whether the activation of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (Erk1/2) are involved in the induction of MMP-9 in lipopolysaccharide (LPS)-stimulated primary astrocytes. The expression of MMP-9 but not MMP-2 was increased by LPS. LPS treatment induced activation of Erk1/2 within 30 min, which was dose-dependently inhibited by PD98059, a specific inhibitor of the Erk kinase (MEK). In this condition, PD98059 blocked the increase in MMP-9 protein and mRNA level as well as gelatin-digesting activity. Inhibition of PKC activity blocked the LPS-induced activation of Erk1/2 as well as MMP-9 expression. In addition, activation of PKC by phorbol myristoyl acetate (PMA) activated Erk1/2 with concomitant increase in MMP-9 production. Moreover, treatment of PD98059 dose-dependently decreased the PMA-induced MMP-9 expression. The results from the present study suggest that induction of MMP-9 by LPS in rat primary astrocytes is mediated, at least in part, by the sequential activation of PKC and Erk1/2. The Erk1/2-mediated MMP-9 induction may provide insights into the regulation of MMP-9 production in CNS, which may occur in vivo in pathological situations such as CNS inflammation.
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PMID:Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated primary astrocytes is mediated by extracellular signal-regulated protein kinase 1/2 (Erk1/2). 1246 42

Studies on B lymphocyte signalling pathways using B lymphocytes from genetically modified mice have the disadvantages of primary cell polyclonality and finite life span. B lymphoma cell lines have been generated from mice with targeted mutations in the oct-2, OBF-1, vav-1 and btk genes, as a model system that lacks these limitations and possesses additional potential for experimental manipulation. To assess their utility, activation of the B cell receptor using anti- micro, the Toll-like receptor-4 using lipopolysaccharide and the interleukin-4 receptor were assessed in these cell lines. Differential tyrosine phosphorylation of intracellular proteins was measured in the wild-type controls compared to the corresponding mutant cell lines after B cell receptor stimulation. Intracellular calcium (Ca2+i) was mobilized in the control cell lines but not in the OBF-1 and Vav1-deficient cells, while Xid B cell lines (btk mutant) showed a reduced Ca2+ mobilization. Extracellular signal-regulated kinase 1/2 phosphorylation in response to anti- micro or lipopolysaccharide stimulation was significantly reduced in Vav1-deficient cells. Interleukin-4 stimulation of wild-type cells resulted in a 2-3-fold increase in Stat-6 phosphorylation. These results indicate that the cell lines mimic the biochemical responses of the corresponding primary B cells. They therefore represent a useful model system to investigate the regulation and roles of these and other gene products in B cell signal transduction and activation.
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PMID:Knockout B lymphoma cell lines as biochemical tools to explore multiple signalling pathways. 1284 51

Novel endotoxin-tolerance was observed to the cytotoxycity induced by lipopolysaccharide (LPS) and cycloheximide (CHX) in an LPS-treated macrophage-like cell line, J774.1; preincubation of macrophages with low doses of LPS alone for 90 min almost completely prevented the apoptotic death in the second incubation with LPS and CHX. The first challenge of LPS affected neither the subsequent LPS binding nor the expression of CD14. Instead, phosphorylation of mitogen-activated proteinkinase (MAP kinases) involving p38, extracellular signal-regulated kinase 1/2 (Erk1/Erk2) and c-jun N-terminal kinase (JNK) in the second incubation with LPS and CHX were suppressed, suggesting that this endotoxin-tolerance was caused by down-regulation of LPS-signaling pathway leading to MAP kinase activation. On the other hand, LPS-induced cytotoxicity seemed to depend on the sustained phosphorylation of p38 MAP kinase; the addition of SB202190, an inhibitor of p38 MAP kinase activity, in the first incubation with LPS caused induction of the cytotoxicity in the second incubation with LPS and CHX or CHX alone, under which conditions increased phosphorylation of p38 MAP kinase without that of Erk1/Erk2 or JNK was observed. These results suggest that down-regulation of the p38 MAP kinase cascade in the first incubation with LPS is linked to induction of endotoxin-tolerance to the cytotoxicity with higher doses of LPS and CHX.
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PMID:Endotoxin-tolerance to the cytotoxicity toward a macrophage-like cell line, J774.1, induced by lipopolysaccharide and cycloheximide: role of p38 MAPK in induction of the cytotoxicity. 1295 67


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