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)

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of cytokine signaling, is expressed in breast cancer cells where it can modify sensitivity and responsiveness to cytokine signaling through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Although it is widely accepted that SOCS3 expression is in itself regulated by STATs, we and others have shown that prostaglandins can also up-regulate SOCS3 expression. Here we used T47D breast cancer cells treated with prostaglandin E2 (PGE2) to examine this pathway. T47D cells responded to PGE2 stimulation with a significant increase in SOCS3 mRNA that was independent of de novo protein synthesis. PGE2 stimulation resulted in STAT3 serine and tyrosine phosphorylation, although mutation of either of the two previously characterized STAT response elements on the SOCS3 promoter did not affect SOCS3 promoter activation by PGE2. In addition, overexpression of STAT3 wild-type, constitutively active or dominant-negative constructs did not affect PGE2-induced SOCS3 promoter activation, indicating that STATs are unlikely mediators of this pathway in these cells. PGE2 is a known activator of the cAMP/protein kinase A (PKA) pathway, and in T47D cells, up-regulation of SOCS3 mRNA by PGE2 was abolished by pretreatment with H89, a PKA inhibitor and increased by cAMP and forskolin treatment. Consistent with this, PGE2 treatment increased cAMP response element (CRE)-binding protein serine phosphorylation. However, mutation of the activator protein 1/CRE on the promoter did not affect basal or PGE2-stimulated activation, suggesting a role for cAMP/PKA that is independent of CRE-binding protein binding. Mutation of the GC-rich region of the SOCS3 promoter, a putative Sp1/Sp3 binding site, abolished both basal and PGE2-stimulated activation. Gel-shift assays showed increased complex formation after treatment, and this was inhibited by the addition of an Sp1 antibody or pretreatment with PKA inhibitor. Chromatin immunoprecipitation assay verified Sp1 binding to the promoter in response to PGE2. Sp1 overexpression increased SOCS3 promoter activation, and both basal and PGE2-induced SOCS3 mRNA expression was prevented by mithramycin, an inhibitor of Sp1 DNA binding. Finally, a physiological role for PGE2 was demonstrated with PGE2 pretreatment reducing lipopolysaccharide-induced STAT3 activation. Collectively, this study details a novel mechanism of SOCS3 up-regulation by PGE2 in breast cancer cells that appears to be STAT independent and involve Sp1 binding to the promoter. This process has possible implications for cytokine responsiveness and tumor progression.
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PMID:Characterization of the SOCS3 promoter response to prostaglandin E2 in T47D cells. 1763 39

Transcription factor C/EBPs are involved in the regulation of various cellular responses. Here, it was suggested that C/EBPdelta gene was activated by lipopolysaccharide (LPS) through transcription factors Sp1, c-Rel, and c-Jun. Assay of the luciferase reporter vectors containing a 5'-deletion of the C/EBPdelta gene promoter indicated that a LPS-responsive element was positioned between -345 and -35 bp of mouse C/EBPdelta gene promoter. Transcription factors Sp1, c-Rel, and c-Jun bound to this region were identified using both in vivo chromatin immunoprecipitation and in vitro DNA-protein binding assays. LPS enhanced the proteins and DNA binding capacities of c-Rel and c-Jun, and the downstream Sp1 site was essential for LPS-induced C/EBPdelta gene. Treatment of cells with ERK/JNK/p38 inhibitors or NF-kappaB inhibitor inhibited the LPS-induced C/EBPdelta gene expression by inhibiting c-Jun, c-Rel, and p300 binding to DNA. Our findings provide a better understanding of LPS-induced C/EBPdelta gene expression.
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PMID:Role of transcriptional factors Sp1, c-Rel, and c-Jun in LPS-induced C/EBPdelta gene expression of mouse macrophages. 1796 28

Hypoxia-inducible factor-1 (HIF-1), the key transcription factor of hypoxia-inducible genes, is known to be involved in inflammation and immune response, but little is known about the regulation of HIF-1 during microglial activation. Thus, we examined effect of lipopolysaccharide (LPS) on HIF-1 activation and its signaling mechanism in BV2 microglial cells. LPS induced HIF-1alpha mRNA and protein expression as well as HIF-1 transcriptional activation. Moreover, HIF-1alpha knockdown by small interfering RNA (siRNA) decreased LPS-induced expression of hypoxia responsive genes, VEGF, iNOS, and COX-2. We then showed that LPS-induced HIF-1alpha mRNA expression was blocked by an antioxidant, NADPH oxidase inhibitors, and siRNA of gp91phox, a subunit of NADPH oxidase. In addition, we showed that specific pharmacological inhibitors of PI 3-kinase and protein kinase C decreased LPS-induced HIF-1alpha mRNA expression. Finally, we showed that inhibition of transcription factor Sp1 by mithramycin A or Sp1 siRNA decreased LPS-induced HIF-1alpha mRNA and protein expression. Consistently, LPS increased Sp1 DNA binding and its transcriptional activity. Taken together, these results suggest that LPS induces HIF-1alpha mRNA expression and activation via NADPH oxidase and Sp1 in BV2 microglia.
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PMID:Lipopolysaccharide induces hypoxia-inducible factor-1 alpha mRNA expression and activation via NADPH oxidase and Sp1-dependent pathway in BV2 murine microglial cells. 1816 13

Nobiletin is a citrus polymethoxylated flavonoid extracted from Citrus depressa, and has several reported biological effects. In this study, we investigated the effect of nobiletin on bacterial lipopolysaccharide (LPS)-induced expression of tissue factor (TF), a trigger protein for the blood coagulation cascade, and studied the possible mechanism of TF transcriptional regulation. THP-1 monocytic cells stimulated with LPS showed an increased expression of both TF protein and mRNA levels. However, pretreatment with nobiletin resulted in inhibition of LPS-induced expression of both TF protein and mRNA in a dose-dependent manner. Electrophoretic mobility shift assays revealed that binding of nuclear proteins from LPS-stimulated THP-1 cells to the NF-kappaB or AP-1 binding motif was increased as compared to non-stimulated control cells. Such increased binding activities were significantly reduced by pretreatment with nobiletin. Binding activity of nuclear proteins to the Sp1 binding motif was observed irrespective of LPS stimulation, but Sp1 activation was inhibited by nobiletin treatment of the cells. Treatment of THP-1 cells with Sp1-specific small interfering RNA (Sp1 siRNA) abolished the ability of LPS to induce TF activity. A similar reduction in the level of TF mRNA was also observed upon treatment of cells with Sp1 siRNA. These studies reveal that constitutive Sp1 activation is an essential event for transcriptional activation of TF, and nobiletin prevents LPS-induced TF expression by inhibiting NF-kappaB, AP-1, and Sp1 activation.
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PMID:Sp1 is an essential transcription factor for LPS-induced tissue factor expression in THP-1 monocytic cells, and nobiletin represses the expression through inhibition of NF-kappaB, AP-1, and Sp1 activation. 1826 12

The objectives of this study were to evaluate the influence of the -1087 single nucleotide polymorphism (SNP) on the gene expression of interleukin (IL)-10 and to identify transcription factors binding to this site in B cells. Using electrophoretic mobility-shift assays and nuclear extract from the DG75 B-cell line, we demonstrated that the Sp1 transcription factor bound to the -1087 G-allele of the IL-10 promoter and that the transcription factors PU.1 and Spi-B bound to both the G- and A-alleles. Transient transfections showed that lipopolysaccharide stimulation resulted in a 15-fold increase in promoter activity for the G-allele as compared to a 6-fold increase for the A-allele. Co-transfection with Sp1 expression vector in Sp1-deficient SL2 cells leading to Sp1 binding to the G-allele of the -1087 SNP resulted in increased IL-10 promoter activity. The results suggest a role for Sp1 transcription factor in the activation of IL-10 through the G-allele of the -1087 SNP in response to inflammatory signals.
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PMID:The Sp1 transcription factor binds to the G-allele of the -1087 IL-10 gene polymorphism and enhances transcriptional activation. 1884 77

Defensins are a group of cationic antimicrobial peptides which play an important role in the innate immune system by exerting their antimicrobial activity against pathogens. In this study, we cloned a novel beta-defensin cDNA from medaka (Oryzias latipes) by rapid amplification of cDNA ends (RACE) technique. The full-length cDNA consists of 480 bp, and the open reading frame (ORF) of 189 bp encodes a polypeptide of 63 amino acids (aa) with a predicted molecular weight of 7.44 kDa. Its genomic organization was analyzed, and Southern blot detection confirmed that only one copy of beta-defensin exists in the medaka HNI strain. RT-PCR, Western blot and immunohistochemistry detections showed that the beta-defensin transcript and protein could be detected in eyes, liver, kidney, blood, spleen and gill, and obviously prevalent expression was found in eyes. Antimicrobial activity of the medaka beta-defensin was evaluated, and the antibacterial activity-specific to Gram-negative bacteria was revealed. Furthermore, the lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, was demonstrated to be able to induce about 13-fold up-regulation of the beta-defensin within first 12h. In addition, promoter and promoter mutagenesis analysis were performed in the medaka beta-defensin. A proximal 100 base pair (bp) sequence (+26 to -73) and the next 1700 bp sequence (-73 to -1755) were demonstrated to be responsible for the basal promoter activity and for the transcription regulation. Three nuclear factor kappa B (NF-kappaB) cis-elements and a Sp1 cis-element were revealed by mutagenesis analysis to exist in the 5' flanking sequence, and they were confirmed to be responsible for the up-regulation of medaka beta-defensin stimulated by LPS. And, the Sp1 cis-element was further revealed to be related to the basal promoter activity, and transcriptional factor II D (TFIID) was found to be in charge of the gene transcription initiation. All the obtained data suggested that the novel medaka beta-defensin should have antimicrobial activity-specific to Gram-negative bacteria, and the antibacterial immune function should be modulated by NF-kappaB and Sp1.
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PMID:Antimicrobial activity-specific to Gram-negative bacteria and immune modulation-mediated NF-kappaB and Sp1 of a medaka beta-defensin. 1908 54

The cytidine deaminase AID (encoded by Aicda in mice and AICDA in humans) is critical for immunoglobulin class-switch recombination (CSR) and somatic hypermutation (SHM). Here we show that AID expression was induced by the HoxC4 homeodomain transcription factor, which bound to a highly conserved HoxC4-Oct site in the Aicda or AICDA promoter. This site functioned in synergy with a conserved binding site for the transcription factors Sp1, Sp3 and NF-kappaB. HoxC4 was 'preferentially' expressed in germinal center B cells and was upregulated by engagement of CD40 by CD154, as well as by lipopolysaccharide and interleukin 4. HoxC4 deficiency resulted in impaired CSR and SHM because of lower AID expression and not some other putative HoxC4-dependent activity. Enforced expression of AID in Hoxc4(-/-) B cells fully restored CSR. Thus, HoxC4 directly activates the Aicda promoter, thereby inducing AID expression, CSR and SHM.
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PMID:HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. 1936 84

Little has been known about Tlr13 (Toll-like receptor 13), a novel member of the Toll-like receptor family. To elucidate the molecular basis of murine Tlr13 gene expression, the activity of the Tlr13 gene promoter was characterized. Reporter gene analysis and electrophoretic mobility shift assays demonstrated that Tlr13 gene transcription was regulated through three cis-acting elements that interacted with the Ets2, Sp1, and PU.1 transcription factors. Furthermore, our work suggests that these transcription factors may cooperate, culminating in maximal transcription of the Tlr13 gene. In contrast, NF-kappaB appeared to act as an inhibitor of Tlr13 transcription. Overexpression of Ets2 caused a strong increase in the transcriptional activity of the Tlr13 promoter; however, overexpression of NF-kappaB p65 dramatically inhibited it. Additionally, interferon-beta is capable of acting Tlr13 transcription, but the activated signaling of lipopolysaccharide/TLR4 and peptidoglycan/TLR2 strongly inhibited the Tlr13 gene promoter. Thus, these findings reveal the mechanism of Tlr13 gene regulation, thereby providing insight into the function of Tlr13 in the immune response to pathogen.
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PMID:Transcriptional regulation of the novel Toll-like receptor Tlr13. 1948 1

Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5'-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.
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PMID:A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis. 1967 82

Interleukin (IL)-10 is an important cytokine in immune regulation and promotes B-cell proliferation and antibody production. High levels of IL-10 were found in subjects with autoimmune diseases. The A to G single nucleotide polymorphism at -1087 of the IL-10 promoter is associated with differences in promoter activity and IL-10 production. The objectives of this study were to analyze differences in the transcription factor binding to the -1087 IL-10 gene polymorphism in B-cells, the influence of the A to G transition on the IL-10 and Sp1 gene expression in B-cells after lipopolysaccharide (LPS) stimulation and the effect of knockdown of Sp1 on IL-10 gene expression. Using B-cell lines obtained from subjects with GG and AA genotypes for the -1087 polymorphism and chromatin immunoprecipitation assay, we showed that the transcription factors PU.1 and Spi-B bound to both G and A alleles, whereas the transcription factor Sp1 only bound to the G allele. LPS stimulation of the B-cells resulted in a larger increase in IL-10 and Sp1 gene expression for GG genotypes than AA genotypes and knockdown of Sp1 gene expression resulted in a decrease in IL-10 mRNA transcription. IL-10 production was higher for the GG genotype than for the AA genotype.
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PMID:Sp1 binds to the G allele of the-1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production. 2007 43


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