Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of interleukin-6 (IL-6) gene expression is mediated by numerous agents involving all major signal transduction pathways. We have compared the effects of prostaglandins and their second messenger cyclic AMP (cAMP) with the effect of lipopolysaccharide (LPS) on IL-6 gene expression. We demonstrate that secretion of IL-6 is induced by cAMP in murine monocytic PU5-1.8 cells, even though to a lesser extent than by LPS. Nevertheless, cAMP and prostaglandins of the E series in the presence of theophylline induce transcription of the IL-6 promoter more strongly than LPS, suggesting distinctive effects of cAMP and LPS on posttranscriptional events. Mutations within four regulatory elements, namely, the multiple response element (MRE), AP-1, NF-IL6, and NF-kappa B sites, significantly reduce, but do not completely abrogate, inducibility by cAMP and prostaglandin E1, whereas alterations of four additional sites have no effects. LPS-induced promoter activity, however, is almost completely abolished by mutations in the NF-kappa B site, suggesting that a single regulatory element is crucial for inducibility by LPS. Stimulation by cAMP is correlated with the binding of inducible factors to the AP-1, NF-IL6, and NF-kappa B elements, whereas factors binding to the MRE are constitutively expressed. Recombinant cAMP response element-binding protein binds to the MRE, indicating a potential role for this factor in the cAMP response. Our results suggest that cAMP and prostaglandins act through multiple, partially redundant regulatory elements to induce IL-6 expression in monocytic cells. Nuclear events that overlap partially with the LPS response but also exhibit distinctive features are involved.
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PMID:Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. 800 51

The tumor necrosis factor alpha (TNF-alpha) promoter contains an AP-1/CRE-like binding site, TGAGCTCA. AP-1 elements generally transduce signals involving protein kinase C; the CRE site mediates a cAMP response, involving protein kinase A. Thus, this element has the potential to receive signals through divergent signaling pathways. Nuclear protein binding studies using extracts from THP-1 monocytic cells treated with lipopolysaccharide (LPS), which stimulates, or dexamethasone (Dex) or pentoxifylline (PTX), which inhibit TNF production, respectively, suggest that two low-mobility complexes could be involved in regulation through this promoter region. PTX and Dex increase binding of both these complexes compared with untreated cells; approximately 2 hours after LPS induction, the upper complex becomes undetectable. This upper complex is composed of ATF2 (activating transcription factor 2, a cyclic AMP responsive element binding protein) homodimers; the lower is a heterodimer of jun/ATF2. LPS induces c-jun and thus may enhance formation of jun/ATF2 complexes, which could be activating complexes. In this case, the simultaneous presence of both complexes, which would occur in the presence of Dex or PTX, could reduce the amount of TNF transcription through competitive binding. Through in vitro competitive binding studies comparing the binding affinities of the TNF promoter sequence and a consensus CRE, we further suggest how variation of endogenous binding sequences from consensus may be an important property for regulatory control of particular genes.
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PMID:Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene. 802 67

Human immunodeficiency virus type 1 (HIV-1) negative factor (Nef) has been shown to down-regulate the transcription factors NF-kappa B and AP-1 in vitro. To define the mechanism of action of the Nef protein, the signal transduction pathways which may be affected in T cells by constitutive expression of the nef gene were examined. Stimulation of T cells with tumor necrosis factor, interleukin-1, or lipopolysaccharide resulted in the recruitment of transcriptional factors to a similar level whether or not the cells expressed the nef gene. On the other hand, stimulation of T cells by mitogens or antibodies to the T-cell receptor (TCR)-CD3 complex resulted in the down-regulation of transcriptional factors NF-kappa B and AP-1 in cells expressing the nef gene compared with cells not expressing the nef gene. Because the Nef protein does not affect the surface expression of the CD3-TCR complex, we conclude that the Nef protein down-regulates the transcriptional factors NF-kappa B and AP-1 in T cells in vitro through an effect on the TCR-dependent signal transduction pathway.
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PMID:Human immunodeficiency virus type 1 Nef protein down-regulates transcription factors NF-kappa B and AP-1 in human T cells in vitro after T-cell receptor stimulation. 815 86

Some antioxidants, including butylated hydroxyanisole (BHA), tetrahydropapaveroline (THP), nordihydroguiauretic acid, and 10,11-dihydroxyaporphine (DHA), were found to be potent inhibitors of the production of tumor necrosis factor (TNF)-alpha, IL-1 beta, and IL-6 by human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS) (IC50s in the low micromolar range). Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis. Inhibition of cytokine production by PBMC was observed also when other inducers were used (staphylococci, silica, zymosan). Much higher concentrations of other antioxidants--including ascorbic acid, trolox, alpha-tocopherol, butylated hydroxytoluene, and the 5-lipoxygenase inhibitor zileuton--did not affect the production of these cytokines. The active compounds did not inhibit IL-1-induced production of IL-6 in fibroblasts, showing the cell selectivity of the effect. Antioxidant-mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs. Nuclear run-on experiments showed that THP inhibited transcription of the IL-1 beta gene. THP decreased the concentration of the transcription factors NF-kappa B and AP-1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS. THP and DHA markedly decreased the levels of TNF-alpha and IL-1 beta in the circulation of mice following LPS injection. Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro-inflammatory cytokines. Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock.
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PMID:Some antioxidants inhibit, in a co-ordinate fashion, the production of tumor necrosis factor-alpha, IL-beta, and IL-6 by human peripheral blood mononuclear cells. 818 92

We implicated deregulated c-Fos/AP-1 in proliferative response of B lymphocytes stimulated with lipopolysaccharide (LPS) using splenic B cells from c-fos transgenic (Mx-c-fos) mice. Levels of DNA synthesis of the Mx-c-fos B cells were augmented in proportion to the amount of AP-1. Since the number of LPS-responding splenic B cells from Mx-c-fos mice was similar to that from control mice duplication time of the Mx-c-fos B cells (0.9 days) was much shorter than that of the control B cells (2.1 days), this augmentation is explained by the acceleration of cell cycle progression by deregulated c-Fos/AP-1. These results suggest that AP-1 is a major regulatory factor for cell cycle progression of B cells activated with LPS.
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PMID:Deregulated c-Fos/AP-1 accelerates cell cycle progression of B lymphocytes stimulated with lipopolysaccharide. 852 56

Inflammation is characterized by the migration of polymorphonuclear leukocytes from the vasculature into the tissue causing profound injury. Adhesion and migration of neutrophils across the vascular bed are governed by a series of complex events including cytokine/chemokine production which in turn orchestrates the temporal expression of a cohort of adhesion molecules mediating the migration. Many of these adhesion molecules and their inducers are under the control of inflammatory response transcriptional factors such as NF kappa B and AP-1. Recently we showed tepoxalin, previously known as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, to be a potent inhibitor of NF kappa B-induced transcription in vitro. In this study, we demonstrated that when administered in vivo, tepoxalin but not naproxen (a nonsteroidal anti-inflammatory drug, NSAID) or zileuton (an LO inhibitor), effectively inhibits neutrophil migration into inflammatory sites in murine skin stimulated by either lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Immunohistochemical analysis indicates that 10-50 mg/kg of tepoxalin inhibits neutrophil migration. It also effectively blocks the upregulation of Mac-1 (CD11b/CD18) on neutrophils. Quantitative polymerase chain reaction Mac-1 analysis shows that LPS-induced transcription of E-selectin mRNA was dramatically suppressed by both 25 and 50 mg/kg of tepoxalin, whereas the level of ICAM-1 was only affected by 50 mg/kg of tepoxalin. Since it has been documented that the expression of E-selectin and Mac-1 is regulated either directly or indirectly by the transcription factor NF kappa B, our studies provide in vivo evidence that tepoxalin is a potent inhibitor of NF kappa B-mediated events in animal models and this novel molecular mechanism clearly defines it as a new class of anti-inflammatory compounds.
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PMID:Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression. 856 54

Activation of macrophages by bacterial lipopolysaccharide (LPS) induces transcription of genes that encode for proinflammatory regulators of the immune response. Previous work has suggested that activation of the transcription factor activator protein 1 (AP-1) is one LPS-induced event that mediates this response. Consistent with this notion, we found that LPS stimulated AP-1-mediated transcription of a transfected reporter gene in the murine macrophage cell line RAW 264.7. As AP-1 activity is regulated in part by activation of the c-Jun N-terminal kinase (JNK), which phosphorylates and subsequently increases the transcriptional activity of c-Jun, we examined whether LPS treatment of macrophages resulted in activation of this kinase. LPS treatment of RAW 264.7 cells, murine bone marrow-derived macrophages, and the human monocyte cell line THP-1 resulted in rapid activation of the p46 and p54 isoforms of JNK. Treatment with wild-type and rough mutant forms of LPS and synthetic lipid A resulted in JNK activation, while pretreatment with the tyrosine kinase inhibitor herbimycin A inhibited this response. Binding of LPS-LPS binding protein (LBP) complexes to CD14, a surface receptor that mediates many LPS responses, was found to be crucial, as pretreatment of THP-1 cells with the monoclonal antibody 60b, which blocks this binding, inhibited JNK activation. These results suggest that LPS activation of JNK in monocyte/macrophage cells is a CD14- and protein tyrosine phosphorylation-dependent event that may mediate the early activation of AP-1 in regulating LPS-triggered gene induction.
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PMID:Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. 861 Jan 16

In human monocytes, interleukin 1beta protein production and steady state mRNA levels are increased in response to lipopolysaccharide, predominantly as a result of increased transcription of the interleukin 1beta gene. Expression of interleukin 1beta and other cytokines, such as interleukin 6 and tumor necrosis factor alpha, has been shown to be dependent on the activation of the transcription factor, NFkappaB. Since recent studies have shown that lipopolysaccharide-induced tyrosine kinase activation is not required for NFkappaB nuclear translocation, we sought to determine whether NFkappaB translocated in the absence of tyrosine kinase activity was active in stimulating transcription. We have found that, in the human pro-monocytic cell line, THP-1, the lipopolysaccharide-induced expression of interleukin 1beta is dependent on tyrosine kinase activation. Tyrosine kinases are not required for lipopolysaccharide-mediated nuclear translocation of NFkappaB. However, in the absence of tyrosine kinase activity, the ability of NFkappaB to stimulate transcription is impaired. This inhibition of transcription is specific for NFkappaB; in the absence of tyrosine kinase activity, AP-1-dependent transcription is enhanced. These results suggest that, while lipopolysaccharide-induced expression of inflammatory mediators requires tyrosine kinase activity, tyrosine kinase activity is not obligatory for lipopolysaccharide signal transduction.
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PMID:Protein-tyrosine kinase activation is required for lipopolysaccharide induction of interleukin 1beta and NFkappaB activation, but not NFkappaB nuclear translocation. 870 66

The development of the technological armamentarium of molecular biology has revolutionized biomedical research in general and nephrologic investigation in particular. In addition to the recent identification of several genes involved in normal kidney function and pathologic conditions, our knowledge regarding the role of cytokines in primary renal diseases, transplant rejection, and dialysis effects has expanded greatly. In particular, molecular biologic methodology has provided insight into the mechanisms controlling cytokine gene regulation, which occurs primarily at the transcriptional level and is mediated by DNA-binding proteins interacting with specific recognition motifs in genetic promoter and enhancer elements. Interleukin-6 (IL-6) is discussed as an example because it is a secretory product of mesangial cells and participates in the cytokine network that determines glomerular and interstitial inflammation. In our analysis of IL-6 gene regulation employing reporter gene and electrophoretic mobility shift assays, we have found that bacterial lipopolysaccharide and cyclic adenosine monophosphate synergistically induce IL-6 expression in macrophages through at least four transcription factors, including AP-1, cAMP-responsive element-binding protein (CREB), NF-IL6, and NF-kappa B. One of the most exciting areas of future research will focus on transcription factor activation in experimental and clinical disease states. Novel therapeutic approaches targeting transcriptional regulation are currently being explored.
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PMID:Molecular biology of cytokines. 872 24

Tissue factor (TF) is inducibly expressed within the vasculature by monocytes and endothelial cells. Transcriptional activation of the TF gene in these two cell types by bacterial lipopolysaccharide (LPS) or cytokines appears to be regulated by a common mechanism. Functional studies identified a 56-bp LPS response element which contains two AP-1 sites and a kappaB site. Assembly of a multiprotein complex composed of Fos-Jun and c-Rel-p65 heterodimers is required to induce TF gene transcription. Inhibiting proteolytic degradation of IkappaBalpha prevents nuclear translocation of c-Rel-p65 heterodimers and blocks inducible TF expression in monocytic and endothelial cells.
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PMID:Regulation of tissue factor gene expression in human monocytic and endothelial cells. 890 67


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