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)

Polycyclic aromatic hydrocarbons (PAH) contained in fossil fuel combustion particles enhance the allergic response to common environmental Ags. A key question is: what are molecular pathways in the immune system by which PAH and conversion products drive allergic inflammation? Circumstantial evidence suggests that macrophages are involved in PAH-induced responses. We demonstrate that a representative PAH, beta-napthoflavone (BNF), and a representative quinone metabolite, tert-butylhydroxyquinone (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activator protein-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage cell lines. Activation of mitogen-activated protein kinases was dependent on generation of oxidative stress, and could be inhibited by N-acetylcysteine. Another genetic response pathway linked to PAH is the antioxidant response element (ARE), which regulates expression of detoxifying enzymes. BNF and tBHQ activated a human ARE (hARE) reporter gene in RAW264.7 cells. Interestingly, bacterial lipopolysaccharide also induced hARE/chloramphenicol acetyltransferase activity. While the hARE core, GTGACTCAGC, contains a consensus AP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and their conversion products operate via ARE-specific transcription factors in the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/chloramphenicol acetyltransferase activation. This suggests that AP-1 proteins negatively regulate the hARE. These data establish important activation pathways for PAH in the immune system and provide us with targets to modulate the effect of environmental pollutants on allergic inflammation.
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PMID:Macrophage activation by polycyclic aromatic hydrocarbons: evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements. 967 Sep 73

D-type cyclins are induced in response to mitogens and are essential and rate-limiting for G1 phase progression in normal mammalian cells. Macrophages proliferating in response to colony-stimulating factor-1 (CSF-1) express cyclin D1 and to a lesser extent cyclin D2 but not cyclin D3. Previously we showed that the macrophage-activating agent lipopolysaccharide (LPS) blocks CSF-1-induced proliferation and cyclin D1 expression in macrophages. Here we report upon the effect of LPS on expression of cyclin D2 in normal mouse bone marrow-derived macrophages (BMM). Unexpectedly we found that this anti-mitogen raised levels of CSF-1-stimulated cyclin D2 mRNA and protein. Furthermore, LPS alone induced cyclin D2 but not cyclin D1. Inhibition of the MEK/ERK (MAPK/ERK kinase/extracellular signal-regulated kinase) mitogen-activated protein kinase pathway repressed LPS-induced cyclin D2 mRNA, whereas inhibition of the p38 mitogen-activated protein kinase enhanced expression. However, in contrast to cyclin D1, cyclin D2 in bone marrow-derived macrophages did not appear to be regulated by protein kinase A pathways. The present data (a) show elevation of a D-type cyclin in the absence of proliferation, (b) demonstrate inverse regulation of two distinct D-type cyclins under identical conditions, and (c) suggest that cyclin D2 plays a role in macrophage activation by LPS.
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PMID:Proliferation-independent induction of macrophage cyclin D2, and repression of cyclin D1, by lipopolysaccharide. 972 38

Inhibitors of p38 mitogen-activated protein kinase (p38) have been reported to block tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production in monocytes at the level of mRNA translation. Yet, several studies document that p38 can phosphorylate and activate specific transcription factors. Thus, to understand better the role of p38 during monocyte activation, we sought to determine the extent to which p38 is required for lipopolysaccharide (LPS)-induced gene expression. For this, differential mRNA display was used to identify LPS-induced genes whose expression was blocked by SB202190, a specific inhibitor of p38. A partial screen identified 10 genes in monoyctes induced 4- to 74-fold by LPS. Of these, genes encoding interferon-induced gene 15, neuroleukin, radiation-inducible immediate-early gene-1, A20, IL-1beta, and superoxide dismutase were suppressed >50% by SB202190. LPS-induced gene activation was not blocked by cycloheximide, indicating that synthesis of intermediate proteins was not required. SB202190 blocked gene induction by 50% when present between 41 and 123 nM, consistent with the potency of this compound as a p38 inhibitor. Furthermore, the ability of SB202190 to block gene activation was stimulus-dependent. LPS and interferon-alpha (IFN-alpha) both up-regulated neuroleukin mRNA, but only LPS-induced neuroleukin mRNA was suppressed by SB202190. In contrast, TNF-alpha and LPS both induced IL-8 mRNA, and induction by either TNF-alpha or LPS was blocked by SB202190. These data were consistent with the ability of LPS and TNF-alpha, but not IFN-alpha, to activate p38 in monocytes. The results provide pharmacological evidence that p38 may be a key mediator of inducible gene expression in monocytes, but its role is stimulus and gene specific.
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PMID:SB202190, a selective inhibitor of p38 mitogen-activated protein kinase, is a powerful regulator of LPS-induced mRNAs in monocytes. 973 69

Macrophages become activated by bacterial endotoxin (lipopolysaccharide) and other stimuli to release proinflammatory cytokines and NO. To prevent release of toxic or potentially lethal quantities of these factors, the state of macrophage activation is counter-regulated by anti-inflammatory mediators (e.g., glucocorticoid hormones, interleukin 10, and transforming growth factor type beta). Fetuin, a negative acute-phase protein, recently was implicated as an anti-inflammatory mediator, because it is required for macrophage deactivation by spermine. In the present studies, we found that fetuin is necessary for macrophages to respond to CNI-1493, a tetravalent guanylhydrazone inhibitor of p38 mitogen-activated protein kinase phosphorylation. Fetuin dose-dependently increases macrophage uptake of CNI-1493, which can be specifically inhibited by anti-human fetuin antibodies. Anti-human fetuin antibodies render primary human peripheral blood mononuclear cells insensitive to deactivation by CNI-1493. Thus, macrophages use fetuin as an opsonin for cationic-deactivating molecules, both endogenous (e.g., spermine) and pharmacologic (e.g., CNI-1493). This role of fetuin as an opsonic participant in macrophage-deactivating mechanisms has implications for understanding and manipulating the innate immune response.
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PMID:Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules. 982 17

p38 mitogen-activated protein kinase (MAPK) is activated by inflammatory stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor. We have previously shown that the pyridinyl imidazole SB 203580, which inhibits it, blocks the interleukin-1 induction of cyclooxygenase-2 (COX-2) and matrix metalloproteinase 1 and 3 mRNAs in fibroblasts. Here we explore the role of p38 MAPK in the response of human monocytes to LPS. 0.1 microM SB 203580 significantly inhibited the LPS induction of COX-2 and tumor necrosis factor protein and mRNAs. The activity of MAPK-activated protein kinase-2 (a substrate of p38 MAPK) in the cells was commensurately reduced. Some isoforms of c-jun N-terminal kinase (which is also activated by LPS) are sensitive to SB 203580; the inhibitor had little effect on monocyte c-jun N-terminal kinases up to 2 microM. We investigated the mechanism of inhibition of COX-2 induction. Transcription (measured by a nuclear run-on assay) was 60% inhibited by SB 203580 (2 microM). Importantly, we found that p38 MAPK was essential for stabilizing COX-2 mRNA: when cells stimulated for 4 h with LPS were treated with actinomycin D, COX-2 mRNA decayed slowly. Treatment of stimulated cells with 2 microM SB 203580 caused a rapid disappearance of COX-2 mRNA, even with actinomycin D present. We conclude p38 MAPK plays a role in the transcription and stabilization of COX-2 mRNA.
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PMID:p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. 986 39

Both the nitrite and prostaglandin E2 (PGE2) release caused by lipopolysaccharide (LPS) in J774 macrophages are inhibited by SB 203580, a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, in a concentration-dependent manner. The 50% inhibitory concentration (IC50) for nitrite and PGE2 responses was 1 microm and 0.5 microm, respectively. Inhibition was marked following simultaneous treatment with SB 203580 and LPS, and was much reduced when SB 203580 was added 6 hr after LPS treatment. In parallel, LPS induction of inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2) proteins and their steady-state levels of mRNA were reduced by SB 203580. LPS activation of nuclear factor-kappa B (NF-kappaB), activator protein-1 (AP-1) and p38 MAPK was also inhibited by SB 203580. These results suggest a crucial role of p38 MAPK in regulation of the transcriptional level of endotoxin LPS-induced iNOS and COX-2 protein expression.
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PMID:Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. 1044 23

The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis. The mechanisms involved in regulating monocyte/macrophage TNFalpha production are not yet fully understood but are thought to involve both soluble factors and cell/cell contact with other cell types. Ligation of certain cell surface receptors, namely CD45, CD44, and CD58, can induce the production of TNFalpha in monocytes. In this paper, we investigate further the signaling pathways utilized by cell surface receptors (specifically CD45) to induce monocyte TNFalpha and compare the common/unique pathways involved with that of lipopolysaccharide. The results indicate that monocyte TNFalpha induced upon CD45 ligation or lipopolysaccharide stimulation is differentially modulated by phosphatidylinositol 3-kinase and nuclear factor-kappaB but similarly regulated by p38 mitogen-activated protein kinase. These results demonstrate that both common and unique signaling pathways are utilized by different stimuli for the induction of TNFalpha. These observations may have a major bearing on approaches to inhibiting TNFalpha production in disease where the cytokine has a pathogenic role.
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PMID:CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-kappaB-independent. 1055 28

STAT1 is an essential transcription factor for macrophage activation by IFN-gamma and requires phosphorylation of the C-terminal Ser727 for transcriptional activity. In macrophages, Ser727 phosphorylation in response to bacterial lipopolysaccharide (LPS), UV irradiation, or TNF-alpha occurred through a signaling path sensitive to the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 whereas IFN-gamma-mediated Ser727 phosphorylation was not inhibited by the drug. Consistently, SB203580 did not affect IFN-gamma-mediated, Stat1-dependent transcription but inhibited its enhancement by LPS. Furthermore, LPS, UV irradiation, and TNF-alpha caused activation of p38 MAPK whereas IFN-gamma did not. An essential role for p38 MAPK activity in STAT1 Ser727 phosphorylation was confirmed by using cells expressing an SB203580-resistant p38 MAPK. In such cells, STAT1 Ser727 phosphorylation in response to UV irradiation was found to be SB203580 insensitive. Targeted disruption of the mapkap-k2 gene, encoding a kinase downstream of p38 MAPK with a key role in LPS-stimulated TNF-alpha production and stress-induced heat shock protein 25 phosphorylation, was without a significant effect on UV-mediated Ser727 phosphorylation. The recombinant Stat1 C terminus was phosphorylated in vitro by p38MAPKalpha and beta but not by MAPK-activated protein kinase 2. Janus kinase 2 activity, previously reported to be required for IFN-gamma-mediated Ser727 phosphorylation, was not needed for LPS-mediated Ser727 phosphorylation, and activation of Janus kinase 2 did not cause the appearance of STAT1 Ser727 kinase activity. Our data suggest that STAT1 is phosphorylated at Ser727 by a stress-activated signaling pathway either through p38 MAPK directly or through an unidentified kinase downstream of p38MAPK.
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PMID:Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. 1057 Jan 80

In this report, we demonstrate that a fetal mouse skin-derived dendritic cell line produces nitric oxide (NO) in response to the endotoxin [lipopolysaccharide (LPS)] and to cytokines [tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Expression of the inducible isoform of NO synthase (iNOS) was confirmed by immunofluorescence with an antibody against iNOS. The tyrosine kinase inhibitor genistein decreased LPS- and GM-CSF-induced nitrite (NO(-2)) production. The effect of LPS and cytokines on NO(-2) production was inhibited by the Janus kinase 2 (JAK2) inhibitor tyrphostin B42. The p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB-203580 also reduced the NO(-2) production evoked by LPS, TNF-alpha, or GM-CSF, but it was not as effective as tyrphostin B42. Inhibition of MAPK kinase with PD-098059 also slightly reduced the effect of TNF-alpha or GM-CSF on NO(-2) production. Immunocytochemistry studies revealed that the transcription factor nuclear factor-kappaB was translocated from the cytoplasm into the nuclei of fetal skin-derived dendritic cells (FSDC) stimulated with LPS, and this translocation was inhibited by tyrphostin B42. Our results show that JAK2 plays a major role in the induction of iNOS in FSDC.
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PMID:Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells. 1060 Jul 56

The effect of extracellular matrix components on lipopolysaccharide-induced vascular endothelial cell injury was studied by using lipopolysaccharide-susceptible bovine aortic endothelial cells. For evaluation of lipopolysaccharide-induced injury, we estimated DNA synthesis and cell detachment of bovine aortic endothelial cells in cultures using extracellular matrix components-coated plastic dishes. Among extracellular matrix components, matrigel almost completely inhibited the reduction in DNA synthesis and the enhancement in cell detachment of bovine aortic endothelial cells in cultures with lipopolysaccharide. The lipopolysaccharide-induced injury was also inhibited by coating with type IV collagen, gelatin, fibronectin, laminin, vitronectin, and heparin sulphate proteoglycan. Extracellular matrix components capable of preventing lipopolysaccharide-induced bovine aortic endothelial cells injury coincidentally inhibited the phosphorylation of p38 mitogen-activated protein kinase in lipopolysaccharide-treated bovine aortic endothelial cells. SB203580, a specific inhibitor of p38 mitogen-activated protein kinase, also prevented the reduction in DNA synthesis and the enhancement in cell detachment of bovine aortic endothelial cells in cultures with lipopolysaccharide. It was therefore suggested that extracellular matrix components might protect bovine aortic endothelial cells from lipopolysaccharide-induced injury through inhibiting the activation of p38 mitogen-activated protein kinase.
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PMID:Extracellular matrix components prevent lipopolysaccharide-induced bovine arterial endothelial cell injury by inhibiting p38 mitogen-activated protein kinase. 1071 20


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