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)

Down-regulation of constitutive hepatic cytochrome P450 (P450) mRNAs by bacterial endotoxin (lipopolysaccharide, LPS) or other inflammatory stimuli has been documented extensively, but the contribution of transcriptional suppression to this effect is poorly understood. Here, we demonstrate that the rates of transcription of the CYP2C11, CYP3A2, and CYP2E1 genes are reduced to 20, 30, and 10% of control levels, respectively, in rat liver within 1 to 2 h of injection of LPS (1 mg/kg). The magnitude and rapidity of these effects indicate that transcriptional suppression is a primary reason for the decline in P450 mRNAs. Injection of curcumin significantly inhibited the rapid transcriptional suppression of CYP2E1, and blocked that of CYP3A2. These effects seemed to be independent of inhibition of nuclear factor-kappaB (NF-kappaB) activation by curcumin, because induction of known NF-kappaB-regulated genes was not attenuated. One hour after LPS injection, the DNA-binding activities of hepatocyte nuclear factor (HNF)1alpha, HNF3beta, and HNF4alpha were reduced to 73, 72, and 53%, respectively, of control values. The nuclear abundances of Sp1, liver-enriched transcriptional inhibitory protein (LIP), HNF1alpha, and HNF3beta were unchanged, whereas the abundance of HNF4alpha was reduced to 87% of control levels. We conclude that changes in Sp1 or LIP do not contribute significantly to the early suppression of P450 transcription in the acute phase rat liver. Although changes in DNA-binding activities of HNF1alpha, HNF3beta, and HNF4alpha are too small individually to explain the observed changes in P450 transcription, the role of each factor in concert with other factors remains to be determined.
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PMID:Rapid transcriptional suppression of rat cytochrome P450 genes by endotoxin treatment and its inhibition by curcumin. 1455 82

Interleukin (IL)-12 is a heterodimeric cytokine consisting of the p40 and p35 chains encoded on separate chromosomes. Coordinated expression of the two constituent genes is crucial for appropriate immune responses in timing, location, and magnitude. Interferon (IFN)-gamma priming of IL-12 production by macrophages represents an important physiological process in vivo for escalated cellular response to microbial infections. We provide evidence that IFN regulatory factor (IRF)-1-deficient macrophages have a selective impairment in mRNA synthesis of IL-12 p35 but not the p40 gene, and a strong deficiency in the production of IL-12 p70 but not p40. We demonstrate that the levels of IL-12 p35 protein stimulated by IFN-gamma and lipopolysaccharide (LPS) correspond to those of its mRNA, and that the nuclear factor kappaB signaling pathway is essential for the induction of IL-12 p35 transcription by LPS. IRF-1 plays a major role in the transcriptional activation of the IL-12 p35 gene, but not of the p40 gene, by physically interacting with an inverted IRF element within the IL-12 p35 promoter upon IFN-gamma activation. Moreover, IRF-1-mediated transcriptional activation of the p35 promoter requires the cooperation of two adjacent Sp1 elements. Thus, IRF-1 acts as a critical component of IFN-gamma signaling in the selective activation of IL-12 p35 transcription in synergy with LPS-mediated events.
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PMID:Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. 1456 84

Restricting transgene expression to specific cell types and maintaining long-term expression are major goals for gene therapy. Previously, we cloned brain-specific angiogenesis inhibitor 1-associated protein 4 (BAI1-AP4), a novel brain-specific protein that interacts with BAI1, and found that it was developmentally upregulated in the adult brain. In this report, we isolated 5 kb of the 5' upstream sequence of the mouse BAI1-AP4 gene and analyzed its promoter activity. Functional analyses demonstrated that an Sp1 site was the enhancer, and the region containing the transcription initiation site and an AP2-binding site was the basal promoter. We examined the ability of the BAI1-AP4 promoter to drive adult brain-specific expression by using it to drive lacZ expression in transgenic (TG) mice. Northern blot analyses showed a unique pattern of beta-galactosidase expression in TG brain, peaking at 1 month after birth, like endogenous BAI1-AP4. Histological analyses demonstrated the same localization and developmental expression of beta-galactosidase and BAI1-AP4 in most neurons of the cerebral cortex and hippocampus. Our data indicate that TG mice carrying the BAI1-AP4 promoter could be a valuable model system for region-specific brain diseases.
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PMID:The promoter of brain-specific angiogenesis inhibitor 1-associated protein 4 drives developmentally targeted transgene expression mainly in adult cerebral cortex and hippocampus. 1514 74

Administration of lipopolysaccharide (LPS) to experimental animals results in the up-regulation of expression of the plasma form of platelet-activating factor acetylhydrolase (PAF AH) in tissue macrophages. To investigate the mechanism underlying induction of PAF AH by LPS we used murine RAW264.7 and human THP-1 macrophages as model systems. We found that the p38 mitogen-activated protein kinase (p38 MAPK) pathway mediates transcriptional activation of the PAF AH gene through the participation of nucleotides -68/-316 relative to the transcriptional initiation site. This promoter region spans two Sp1/Sp3 binding sites (SP-A and SP-B) and is necessary and sufficient for the observed effect. Disruption of these Sp binding sites significantly reduces promoter activity in LPS-stimulated cells. The ability of LPS to induce transcriptional activation of PAF AH is not due to enhanced Sp1/Sp3 binding to the promoter but involves enhanced transactivation function of Sp1 via p38 MAPK activation. These studies characterize the mechanism by which LPS modulates expression of PAF AH at the transcriptional level, and they have important implications for our understanding of responses that occur during the development of LPS-mediated inflammatory diseases.
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PMID:The p38 MAPK pathway mediates transcriptional activation of the plasma platelet-activating factor acetylhydrolase gene in macrophages stimulated with lipopolysaccharide. 1521 49

Macrophage inflammatory protein-2 (MIP-2) is a C-X-C chemokine that is important in recruiting neutrophils to inflammatory sites. Our previous reports demonstrated that lipopolysaccharide (LPS) or CpG-oligode-oxynucleotide (CpG-ODN) rapidly induce MIP-2 gene expression in the macrophage cell line, RAW 264.7. Here, we show that the DNA sequence of the MIP-2 promoter between -114 and +14 is sufficient for strong promoter activity in LPS- or CpG-ODN-stimulated RAW 264.7 cells. Importantly, comprehensive mutant analysis reveals that an Sp1 element in the promoter region between -114 and -94 is essential for synergistic MIP-2 promoter activation by NF-kappaB and c-Jun regardless of the presence of an AP-1 site. By combining deletion or site-specific mutant analysis with immunocomplex assays, we also confirmed that Sp1 mediates the recruitment of transcription factors NF- kappaB and c-Jun in LPS- or CpG-ODN-treated RAW 264.7 cells. Several lines of experimental evidence imply that the Sp1-binding element is an important determinant of MIP-2 promoter activity, and that NF-kappaB, c-Jun and Sp1 can functionally cooperate to elicit maximal activation of the promoter.
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PMID:Sp1-associated activation of macrophage inflammatory protein-2 promoter by CpG-oligodeoxynucleotide and lipopolysaccharide. 1566 90

HIV-1-infected monocyte/macrophages located in lymph nodes and tissues are highly productive sources of HIV-1 and may function as a persistent reservoir contributing to the rebound viremia observed after highly active antiretroviral therapy is stopped. Mechanisms activating latently infected, primary monocyte/macrophages to produce HIV-1 were investigated using monocytes isolated from a transgenic mouse line carrying a full-length proviral clone of a monocyte-tropic HIV-1 isolate, HIV-1(JR-CSF), regulated by the endogenous long terminal repeat (LTR) (JR-CSF mice). Granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with lipopolysaccharide (LPS) induced infectious HIV-1 production by JR-CSF mouse monocytes over 10-fold and 100-fold higher than that stimulated by GM-CSF or LPS alone, respectively. We examined mechanisms of GM-CSF synergy with LPS and demonstrated that GM-CSF up-regulated the LPS receptor, TLR-4, and also synergized with LPS to activate mitogen-activated protein (MAP) kinase/ERK kinase and the Sp1 transcription factor. Inhibitors of either MAP kinase/ERK kinase or p38 kinase but not PI 3-kinase potently suppressed GM-CSF and LPS-induced HIV-1 production by JR-CSF mouse monocytes. Because Sp1 is activated by both the MAP kinase/ERK kinase and p38 kinase pathways, we postulate that synergistic activation of these pathways by GM-CSF and LPS induced sufficient levels of Sp1 to activate the HIV-1 LTR in a Tat-independent manner and induced HIV-1 production by JR-CSF mouse monocytes. Thus, our study delineated the pathway of HIV-1 LTR activation by GM-CSF and LPS and indicated that JR-CSF transgenic mice may provide a new in vitro and in vivo system for investigating the mechanism by which inflammatory and infectious stimuli activate HIV-1 production from latently infected monocytes.
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PMID:Identification of granulocyte-macrophage colony-stimulating factor and lipopolysaccharide-induced signal transduction pathways that synergize to stimulate HIV type 1 production by monocytes from HIV type 1 transgenic mice. 1572 51

Exposure of blood to tissue factor (TF) rapidly initiates the coagulation serine protease cascades. TF is expressed by macrophages and other types of cell within atherosclerotic lesions and plays an important role in thrombus formation after plaque rupture. Macrophage TF expression is induced by pro-inflammatory stimuli including lipopolysaccharide (LPS), interleukin-1beta and tumor necrosis factor-alpha. Here we demonstrate that activation of liver X receptors (LXRs) LXRalpha and LXRbeta suppresses TF expression. Treatment of mouse peritoneal macrophages with synthetic LXR agonist T0901317 or GW3965 reduced TF expression induced by pro-inflammatory stimuli. LXR agonists also suppressed TF expression and its activity in human monocytes. Human and mouse TF promoters contain binding sites for the transcription factors AP-1, NFkappaB, Egr-1 and Sp1, but no LXR-binding sites could be found. Cotransfection assays with LXR and TF promoter constructs in RAW 264.7 cells revealed that LXR agonists suppressed LPS-induced TF promoter activity. Analysis of TF promoter also showed that inhibition of TF promoter activity by LXR was at least in part through inhibition of the NFkappaB signaling pathway. In addition, in vivo, LXR agonists reduced TF expression within aortic lesions in an atherosclerosis mouse model as well as in kidney and lung in mice stimulated with LPS. These findings indicate that activation of LXR results in reduction of TF expression, which may influence atherothrombosis in patients with vascular disease.
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PMID:Liver X receptor agonists inhibit tissue factor expression in macrophages. 1575 69

We have previously reported that NCX 2057, a new chemical entity bearing a nitric oxide (NO)-releasing moiety linked to the natural antioxidant ferulic acid, shows marked anti-inflammatory properties in a model of chronic brain inflammation. We have now studied the effects of NCX 2057 and its metabolic products, ferulic acid and NCX 2059, on inducible nitric oxide synthase (iNOS) expression and function in lipopolysaccharide/interferon-gamma (LPS/IFNgamma)-stimulated RAW 264.7 macrophages. NCX 2057 inhibited iNOS mRNA and protein expression (IC(50)=6.2+/-1.0 microM) without altering iNOS protein degradation rate. NCX 2057 also decreased the levels of LPS/IFNgamma-induced nitrite accumulation (IC(50)=4.3+/-0.7 microM) in RAW 264.7 cells. Conversely, NCX 2059, which does not possess NO-donating properties, was only weakly effective (IC(50) >100 microM) and ferulic acid was inactive. To understand further the mechanisms underlying anti-inflammatory properties we studied the effects of NCX 2057 on selected transcription factors. Unlike ferulic acid, NCX 2057 inhibited LPS-induced translocation/activation of the nuclear factor, NF-kappaB, while other transcription factors, such as, Sp1, NF-IL2A and STAT-1 were not affected. The present data support the concept that NO adds important anti-inflammatory properties to ferulic acid. Thus, NCX 2057 represents a new prototype drug for the treatment of disorders associated with chronic inflammation and oxidative stress.
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PMID:Modulation of iNOS expression by a nitric oxide-releasing derivative of the natural antioxidant ferulic acid in activated RAW 264.7 macrophages. 1644 13

The involvement of Sp1 in the lipopolysaccharide (LPS)-induced transcription of HDC mRNA in the mouse macrophage-like cell line RAW 264 was analyzed. LPS increased the levels of HDC mRNA 4 h after the stimulation in a concentration-dependent manner. Mithramycin A, an inhibitor of the binding of the Sp family to the GC box, reduced the LPS-induced increase in the levels of HDC mRNA at 4 h and HDC protein at 8 h in a concentration-dependent manner. By conducting electrophoretic mobility shift assays, we found that one of the transcription factors binding to the DNA probe containing the GC box sequence of the mouse HDC gene promoter region was Sp1, and that levels of Sp1-DNA probe complexes were increased by stimulation with LPS although the protein levels of Sp1 were not changed. These results suggested that Sp1 is one of the transcription factors that regulate the LPS-induced expression of HDC in RAW 264 cells.
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PMID:Involvement of Sp1 in lipopolysaccharide-induced expression of HDC mRNA in RAW 264 cells. 1694 47

We have previously demonstrated that challenge of rat or mice with lipopolysaccharide (LPS) in vivo promotes Sp1 protein degradation. The protease responsible for the LPS-induced Sp1 degradation has not been identified. In this study, we have identified, characterized and partially purified an LPS-inducible Sp1-degrading enzyme (LISPDE) activity from rat lungs. LISPDE activity selectively degraded Sp1, but not nuclear protein, C-fos, p65, I-kappaBalpha and protein actin. Nuclear extract contains approximately 14-fold of the LISPDE activity as that detected in cytoplasmic extract, suggesting that LISPDE is predominantly a nuclear protease. Using biochemical reagents, protease inhibitors and peptide substrates, we have characterized the LISPDE activity. Based on biochemical characteristics, inhibitor profile, and substrate specificity, we have shown that LISPDE activity is not 26S proteasome, caspase or cathepsin-like activity, but is a trypsin-like serine protease activity. Using soybean trypsin inhibitor (SBTI)-sepharose affinity column, we have partially purified the LISPDE protein, which has an estimated molecular mass of 33 kDa and selectively degrades native Sp1 protein. We mapped the initial site for proteolytic cleavage of Sp1 by LISPDE to be located within the region between amino acids 181-328. We conclude that LPS causes Sp1 degradation by inducing a unique trypsin-like serine protease, LISPDE.
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PMID:Lipopolysaccharide causes Sp1 protein degradation by inducing a unique trypsin-like serine protease in rat lungs. 1709 79


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