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)

Increased expression of tumor necrosis factor alpha (TNFalpha) in response to chronic ethanol has been implicated in the pathogenesis of alcoholic liver disease. However, the molecular mechanisms by which ethanol increases the levels of TNFalpha are not well characterized. Utilizing Kupffer cells isolated from rats fed an ethanol containing diet and a murine macrophage cell line, RAW264.7, exposed to ethanol in culture, we have demonstrated that exposure to chronic ethanol results in an enhanced expression of lipopolysaccharide (LPS)-induced TNFalpha. While chronic ethanol had no effect on the rate of LPS-induced TNFalpha transcription as measured by nuclear run-on experiments, TNFalpha mRNA half-life was increased by chronic ethanol. Chronic ethanol also potentiated the activation of LPS-induced p38 mitogen-activated protein (MAP) kinase in Kupffer cells, as well as in RAW264.7 cells. Specific inhibition of p38 MAP kinase activation by SB203580 in Kupffer cells or by overexpression of dominant negative p38 MAP kinase in RAW264.7 cells blocked ethanol-mediated TNFalpha mRNA stabilization. Furthermore, using chimeric reporter constructs, we have shown that A + U-rich elements in the 3'-untranslated region of TNFalpha mRNA are not sufficient to impart ethanol-mediated stabilization on TNFalpha mRNA.
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PMID:Stabilization of tumor necrosis factor alpha mRNA by chronic ethanol: role of A + U-rich elements and p38 mitogen-activated protein kinase signaling pathway. 1155 56

We have isolated a cDNA homologous to known dual-specificity phosphatases from a mouse macrophage cDNA library and termed it MKP-M (for mitogen-activated protein kinase phosphatase isolated from macrophages). Three other presumed splice variant isoforms have also been identified for MKP-M. The longest and most abundant mRNA contains an open reading frame corresponding to 677 amino acids and produces an 80-kDa protein. The deduced amino acid sequence of MKP-M is most similar to those of hVH-5 (or mouse M3/6) and VHP1, a Caenorhabditis elegans tyrosine phosphatase. It includes an N-terminal rhodanase homology domain, the extended active-site sequence motif (V/L)X(V/I)HCXAG(I/V)SRSXT(I/V)XXAY(L/I)M (where X is any amino acid), and a C-terminal PEST sequence. Northern blot analysis revealed a dominant MKP-M mRNA species of approximately 5.5 kb detected ubiquitously among all tissues examined. MKP-M was constitutively expressed in mouse macrophage cell lines, and its expression levels were rapidly increased by lipopolysaccharide (LPS) stimulation but not by tumor necrosis factor alpha (TNF-alpha), gamma interferon, interleukin-2 (IL-2), or IL-15 stimulation. Immunocytochemical analysis showed MKP-M to be present within cytosol. When expressed in COS7 cells, MKP-M blocks activation of mitogen-activated protein kinases with the selectivity c-Jun N-terminal kinase (JNK) >> p38 = extracellular signal-regulated kinase. Furthermore, expression of a catalytically inactive form of MKP-M in a mouse macrophage cell line increased the intensity and duration of JNK activation and TNF-alpha secretion after LPS stimulation, suggesting that MKP-M is at least partially responsible for the desensitization of LPS-mediated JNK activation and cytokine secretion in macrophages.
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PMID:A novel mitogen-activated protein kinase phosphatase is an important negative regulator of lipopolysaccharide-mediated c-Jun N-terminal kinase activation in mouse macrophage cell lines. 1156 82

Although apoptosis has been observed in macrophages during the course of infections, the mechanism of apoptosis in activated macrophages is not fully understood. This study shows that pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (ZVAD) or t-butyloxycarbonyl-Asp-fluoromethylketone (Boc-D) caused the death of lipopolysaccharide (LPS)-activated macrophages and RAW 264.7 cells with apoptotic features. The apoptosis was also observed in lipoprotein-treated bacteria but not in CpG oligonucleotide- or flagellin-treated macrophages, indicating a difference of cellular responses downstream of different Toll-like receptors. Consistent with the induction of cell death by pan-caspase inhibitors, no activation of known caspases was detected in LPS-ZVAD-treated cells, suggesting an involvement of unknown proapoptotic caspases in the cell death. ZVAD inhibited the activation of extracellular signal-regulated kinase (ERK) and p38 but not of nuclear factor (NF)-kappa B induced by LPS, suggesting that the ZVAD-sensitive molecule lies upstream of the ERK and p38 pathways but downstream of the divergent site of NF-kappa B and mitogen-activated protein kinases. Our results demonstrate that apoptosis of macrophages induced by LPS+ZVAD is independent from the known proapoptotic caspases and suggest that activity of an unidentified ZVAD-sensitive molecule(s) is involved in the survival of LPS-activated macrophages.
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PMID:Apoptosis by pan-caspase inhibitors in lipopolysaccharide-activated macrophages. 1159

Unmethylated CpG motifs in bacterial DNA (CpG DNA) activate host innate immune responses synergistically with some other microbial products, such as endotoxins, and may contribute to disease pathogenesis through excessive production of proinflammatory cytokines. Because monocyte-derived tumor necrosis factor (TNF)-alpha is an important mediator of disease, we investigated whether CpG DNA and lipopolysaccharide (LPS) synergize for inducing TNF-alpha biosynthesis. CpG DNA and LPS synergistically induce TNF-alpha production in RAW264.7 cells and J774 cells through activation of NF-kappaB. Furthermore, transient transfection with a super-repressive mutant of IkappaBalpha (IkappaBalpha-AA) demonstrated that NF-kappaB plays a critical role in CpG DNA-mediated TNF-alpha expression. Like NF-kappaB activation, CpG DNA-induced activation of mitogen-activated protein kinases (MAPK) regulates TNF-alpha production. Both extracellular receptor kinase (ERK) and p38 can regulate TNF-alpha gene transcription induced by CpG DNA. Although CpG DNA at the higher concentration slightly enhanced LPS-mediated phosphorylation of ERK, it did not alter the LPS-mediated activation of c-Jun N-terminal kinase and p38. In addition, CpG DNA showed little or no enhancement of LPS-mediated AP-1 activation. These results suggest that CpG DNA- and LPS-mediated signals converge at or above the level of NF-kappaB and ERK, and that there are distinct, as well as common, signaling pathways which are utilized by both CpG DNA and LPS for activating various transcription factors and MAPK.
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PMID:Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-alpha production through activation of NF-kappaB. 1167 71

Estradiol (E(2)) exerts not only genotropic but also nongenomic actions through nuclear estrogen receptors (ER). Here, we provide a novel paradigm for nongenomic E(2) signaling independent of nuclear ER. E(2) induces a rapid rise in the intracellular free Ca(2+) concentration ([Ca(2+)](i)) through membrane estrogen receptors in murine RAW 264.7 macrophages. This E(2)-induced Ca(2+) signaling is not prevented by different ER blockers and cannot directly activate stably transfected c-fos promoter or the mitogen-activated protein kinases p38, ERK1/2, and SAPK/JNK, or NO production. However, the E(2)-induced rise in [Ca(2+)](i) specifically down-regulates the serum-stimulated activation of c-fos promoter and ERK1/2, and conversely, it specifically up-regulates lipopolysaccharide-stimulated activation of c-fos promoter, p38, and NO production. The E(2)-changed activation of c-fos promoter can be prevented by an intracellular Ca(2+) chelator. Our data indicate that E(2)-induced nongenomic Ca(2+) signaling through membrane ER is able to specifically modulate genotropic signaling pathways with impact on macrophage activation.
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PMID:Estradiol-induced nongenomic calcium signaling regulates genotropic signaling in macrophages. 1175 57

Endotoxin (lipopolysaccharide, LPS) is a component of the outer membrane of Gram-negative bacteria and promotes the activation of macrophages and microglia. Although these cells are highly LPS-responsive, they serve unique tissue-specific functions and exhibit different LPS sensitivities. Accordingly, it was of interest to evaluate whether these biological differences reside in variations within LPS signaling pathways between these two cell types. Because the mitogen-activated protein kinases ERK-1 and ERK-2 have been implicated in the control of many immune responses, we tested the concept that they are a key indicator for differences in cellular LPS sensitivity. We observed that murine RAW 264.7 macrophages and murine BV-2 microglial cells both respond to LPS by exhibiting increased IkappaBalpha degradation, enhanced NF-kappaB DNA binding activity, and elevated nitric oxide and interleukin-1beta production. Although LPS potently stimulates ERK activation in RAW 264.7 macrophages, it does not activate ERK-1/-2 in BV-2 microglia. Moreover, antagonism of the MEK/ERK pathway potentiates LPS-stimulated nitric oxide production, suggesting that LPS-stimulated ERK activation can exert inhibitory effects in macrophage-like cells. These data support the idea that ERK activation is not a required function of LPS-mediated signaling events and illustrate that alternative/additional pathways for LPS action exist in these cell types.
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PMID:A differential role for the mitogen-activated protein kinases in lipopolysaccharide signaling: the MEK/ERK pathway is not essential for nitric oxide and interleukin 1beta production. 1178 32

Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor kappaB) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-alphaa, (TNF-alphaa), IL-1alphab, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor kappaB activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-alphaa, and IL-1alphab. Another signaling cascade by which GSA activates VSMCs is the ERK-->c-Fos-->AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs.
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PMID:Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). 1179 73

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFalpha to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFalpha, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-kappaB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.
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PMID:Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. 1181 69

We examined whether changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione of human monocytes regulate lipopolysaccharide (LPS)-induced IL-12 production and defined the molecular mechanism that underlies glutathione redox regulation. Monocytes exposed to glutathione reduced form ethyl ester (GSH-OEt) or maleic acid diethyl ester (DEM) increased or decreased the intracellular GSH/GSSG ratio, respectively. LPS-induced IL-12 production and p38 mitogen-activated protein (MAP) kinase activation were enhanced by GSH-OEt but suppressed by DEM. Selective p38 inhibitors showed that p38 promoted GSH-OEt-enhanced IL-12 production. Furthermore, IFN-gamma priming increased the GSH/GSSG ratio and enhanced IL-12 production through p38, and DEM negated the priming effect of IFN-gamma on p38 activation and IL-12 production as well as on the GSH/GSSG ratio. These findings reveal that glutathione redox regulates LPS-induced IL-12 production from monocytes through p38 MAP kinase activation and that the priming effect of IFN-gamma on IL-12 production is partly a result of the glutathione redox balance.
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PMID:Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in IFN-gamma priming of IL-12 production. 1181 56

In analyzing the regulation of neurotrophin production/secretion from microglia, C8-ceramide (D-erythro-sphingosine, N-octanoyl-) was found to induce secretion of brain-derived neurotrophic factor (BDNF) from microglia in vitro. In the present study, the action of C8-ceramide in secreting neurotrophic and harmful factors was investigated and compared with the effects of lipopolysaccharide (LPS). C8-ceramide as well as LPS enhanced the production/secretion of BDNF but, different from LPS, did not induce tumor necrosis factor alpha, interleukin-1beta, or nitric oxide. The C8-ceramide-induced BDNF release was significantly suppressed by protein kinase C (PKC) inhibitor, bisindolylmaleimide, which targets PKC isoforms, alpha, beta, gamma, delta and epsilon. However, it was not suppressed by a specific inhibitor of PKCalpha. Furthermore, PKCbeta and gamma were undetected in the microglia. Therefore, PKCdelta and/or epsilon appear to be functioning PKC isoforms. In contrast, none of the mitogen-activated protein kinases (MAPKs) and none of the transcription factors, including the cAMP response element-binding transcription factor (CREB) and nuclear factor kappaB (NFkappaB) were activated in the microglia in response to C8-ceramide. These results indicate that ceramide-induced BDNF release in microglia is mediated by a signaling pathway associated with PKCdelta and/or epsilon, but not with activation of MAPKs, CREB and NFkappaB.
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PMID:Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. 1184 76


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