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)

We have recently isolated two cDNAs encoding two forms of transmembrane and cytosolic protein tyrosine phosphatase epsilon (PTPepsilon). In this study, the 5' end of the rat PTPepsilon gene was isolated and characterized. Transmembrane PTPepsilon (PTPepsilonM) and cytosolic PTPepsilon (PTPepsilonC) were encoded by a single gene. 5' RACE analysis and RNase protection assay showed that the mRNA of each PTPepsilon isoform was transcribed from different promoters. The putative promoter regions of two alternative first exons lacked a TATA box, but contained potential recognition sites for several transcription factors. Reverse transcription PCR analysis revealed that PTPepsilonC mRNA was up-regulated during interleukin 6-induced differentiation of murine leukemia M1 cells, whereas PTPepsilonM mRNA was down-regulated. With the use of luciferase as a reporter gene, the promoter activities of the 5'-flanking regions were examined during phorbol myristate acetate-induced differentiation of HL-60 cells. In the differentiated HL-60 cells, the activity of the PTPepsilonC promoter, but not that of PTPepsilonM, was dramatically elevated. Furthermore, we found that PTPepsilonC mRNA is highly expressed in mouse peritoneal macrophages and enhanced during activation by lipopolysaccharide. These results suggest that the different promoters control expression of PTPepsilon isoforms during the differentiation and/or activation of macrophages.
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PMID:Distinct promoters control transmembrane and cytosolic protein tyrosine phosphatase epsilon expression during macrophage differentiation. 991 74

beta-Defensins are cationic peptides with broad-spectrum antimicrobial activity that are produced by epithelia at mucosal surfaces. Two human beta-defensins, HBD-1 and HBD-2, were discovered in 1995 and 1997, respectively. However, little is known about the expression of HBD-1 or HBD-2 in tissues of the oral cavity and whether these proteins are secreted. In this study, we characterized the expression of HBD-1 and HBD-2 mRNAs within the major salivary glands, tongue, gingiva, and buccal mucosa and detected beta-defensin peptides in salivary secretions. Defensin mRNA expression was quantitated by RNase protection assays. HBD-1 mRNA expression was detected in the gingiva, parotid gland, buccal mucosa, and tongue. Expression of HBD-2 mRNA was detected only in the gingival mucosa and was most abundant in tissues with associated inflammation. To test whether beta-defensin expression was inducible, gingival keratinocyte cell cultures were treated with interleukin-1beta (IL-1beta) or bacterial lipopolysaccharide (LPS) for 24 h. HBD-2 expression increased approximately 16-fold with IL-1beta treatment and approximately 5-fold in the presence of LPS. Western immunoblotting, liquid chromatography, and mass spectrometry were used to identify the HBD-1 and HBD-2 peptides in human saliva. Human beta-defensins are expressed in oral tissues, and the proteins are secreted in saliva; HBD-1 expression was constitutive, while HBD-2 expression was induced by IL-1beta and LPS. Human beta-defensins may play an important role in the innate defenses against oral microorganisms.
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PMID:Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. 1033 76

Alterations in alveolar macrophage (AM) function during sepsis-induced hypoxia may influence tumor necrosis factor (TNF) secretion and the progression of acute lung injury. Nuclear factor (NF)-kappaB is thought to regulate the expression of endotoxin [lipopolysaccharide (LPS)]-induced inflammatory cytokines such as TNF, and NF-kappaB may also be influenced by changes in O2 tension. It is thus proposed that acute changes in O2 tension surrounding AMs alter NF-kappaB activation and TNF secretion in these lung cells. AM-derived TNF secretion and NF-kappaB expression were determined after acute hypoxic exposure of isolated Sprague-Dawley rat AMs. Adhered AMs (10(6)/ml) were incubated (37 degrees C at 5% CO2) for 2 h with LPS (Pseudomonas aeruginosa, 1 microgram/ml) in normoxia (21% O2-5% CO2) or hypoxia (1.8% O2-5% CO2). AM-derived TNF activity was measured with a TNF-specific cytotoxicity assay. Electrophoretic mobility shift and supershift assays were used to determine NF-kappaB activation and to identify NF-kappaB isoforms in AM extracts. In addition, mRNAs for selected AM proteins were determined with RNase protection assays. LPS-exposed AMs in hypoxia had higher levels of TNF (P < 0.05) and enhanced expression of NF-kappaB (P < 0.05); the predominant isoforms were p65 and c-Rel. Increased mRNA bands for TNF-alpha, interleukin-1alpha, and interleukin-1beta were also observed in the hypoxic AMs. These results suggest that acute hypoxia in the lung may induce enhanced NF-kappaB activation in AMs, which may result in increased production and release of inflammatory cytokines such as TNF.
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PMID:Acute hypoxia increases alveolar macrophage tumor necrosis factor activity and alters NF-kappaB expression. 1036 14

The 4555-bp promoter fragment for intracellular interleukin 1 receptor antagonist (4555-bp icIL-1Ra) has recently been demonstrated to regulate gene expression in a cell-type specific manner in vitro in transient transfection studies. To examine the activity of this promoter in vivo, transgenic mice possessing the 4555-bp promoter coupled to the E. coli lacZ reporter gene were created. Expression of endogenous icIL-1Ra and E. coli lacZ mRNA were examined in different tissues by RT-PCR, RNase protection assay and in situ hybridization. In transgenic mice both endogenous icIL-1Ra and E. coli lacZ were co-expressed by keratinocytes and by epithelial cells in different organs of the digestive system. The transgene was also expressed in the brain in four out of five lines, whereas endogenous icIL-1Ra was not detected in this organ. In contrast, only icIL-1Ra mRNA, but not E. coli lacZ mRNA, was detected in lipopolysaccharide (LPS)-stimulated resident peritoneal macrophages from icIL-1Ra promoter transgenic mice. These results indicate that a 4555-bp promoter fragment of human icIL-1Ra appropriately regulates gene transcription in keratinocytes and gastrointestinal epithelial cells in vivo. However, other as yet unidentified regulatory regions influence icIL-1Ra gene expression in macrophages following LPS stimulation.
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PMID:The human intracellular interleukin 1 receptor antagonist promoter appropriately regulates gene expression in keratinocytes and gastrointestinal epithelial cells in vivo. 1043 2

This study determined the effects of feeding status on basal and lipopolysaccharide (LPS)-stimulated cytokine and neuropeptide gene expression in the hypothalamus. With the use of RNase protection assays, we measured mRNA levels of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1RA), IL-1 receptor type I (IL-1RI), IL-1R accessory proteins (AcP I and II), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1 (TGF-beta1), glycoprotein 130 (Gp 130), leptin receptor (OB-R), neuropeptide Y (NPY), preprodynorphin, and proopiomelanocortin (POMC). Analyses were done in ad libitum-fed, fasted, and fasted and refed rats treated with the intracerebroventricular administration of physiological saline or LPS. The data show that food deprivation increases the basal mRNA expression of IL-1beta, IL-1RA, TNF-alpha, IL-1RI, and IL-1R AcP I, whereas mRNA levels of POMC showed a decrease. Five hours of refeeding returned cytokine levels to those observed in the ad libitum-fed group. LPS administration induced a robust upregulation of IL-1beta, TNF-alpha, and IL-1RI during all three feeding conditions. Acute food deprivation did not modulate LPS-induced changes in hypothalamic cytokine mRNA profiles. These findings show that 1) cytokine modulation occurs as an adaptive response to the stress of acute fasting and 2) acute fasting does not affect LPS-induced cytokine mRNA modulation in the hypothalamus. The data have implications to gram-negative infections associated with acute anorexia.
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PMID:Feeding status and bacterial LPS-induced cytokine and neuropeptide gene expression in hypothalamus. 1051 61

Dendritic cells (DC) are highly-specialized antigen-presenting cells (APC), that initiate and modulate immune responses. Their specialized migratory and tissue-homing properties are regulated by small molecular weight proteins (chemokines) that govern leukocyte migration and activation. Little is known about the capacity of liver DC to produce or respond to chemokines. Here we examined chemokine and chemokine receptor (CR) gene expression in both immature DC progenitors (DCp) and comparatively mature DC generated from mouse liver. Factors affecting production of the chemokine macrophage inflammatory protein (MIP)-1alpha, and the influence of MIP-1alpha on liver DC migration were also investigated. Dendritic cells were propagated in response to granulocyte-macrophage colony stimulating factor (GM-CSF) +/- interleukin (IL)-4 from bone marrow (BM) cells or liver non-parenchymal cells (NPC) isolated from normal mice, or from mice treated with the hematopoietic growth factor Flt3 ligand (FL). Their phenotype and allostimulatory function were assessed by monoclonal antibody (mAb) staining and flow cytometry, and by the capacity to induce mixed leukocyte reactions, respectively. Specific chemokine and CR gene expression was studied using the RNase protection assay (RPA). Production of MIP-1alpha was determined by enzyme-linked immunoabsorbent assay (ELISA), and the migratory activity of liver DC induced by MIP-1alpha quantitated using microchemotaxis chambers. Like DC generated simultaneously from BM, liver-derived DC expressed mRNA for a variety of CC and CXC chemokines. RANTES (regulated upon activation, normal T cell expressed and secreted) transcripts were the most strongly expressed. Gene transcripts for the receptor CCR1, that binds RANTES and MIP-1alpha were also readily detected, as was CCR2, the receptor for the monocyte chemotactic proteins (MCP)1-4. No major differences in chemokine or CR mRNA expression were detected between immature and more mature liver DC. MIP-1alpha production by liver-derived DC was stimulated by bacterial lipopolysaccharide (LPS), and high levels were also detected in co-cultures of hepatic DC and allogeneic T cells. Chemotactic migration of liver-derived DC was stimulated by MIP-1alpha. Thus, liver-derived DC express mRNA for several CC and CXC chemokines and their receptors that may play key roles in the regulation of hepatic inflammatory responses. Production of MIP-1alpha by liver DC, and their migratory responses to this chemokine, suggest that MIP-1alpha and other chemokines may play significant roles in the regulation of liver DC function and in interactions of liver DC with other leukocytes, under normal and inflammatory conditions.
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PMID:Chemokine and chemokine receptor expression by liver-derived dendritic cells: MIP-1alpha production is induced by bacterial lipopolysaccharide and interaction with allogeneic T cells. 1083 7

Classic ischemic preconditioning transiently (30 to 120 minutes) protects the myocardium against subsequent lethal ischemia/reperfusion injury. After dissipation of this acute protection, a second window of protection (SWOP) appears 12 to 24 hours later; this SWOP lasts up to 3 days. Several triggers induce a SWOP, including brief repetitive cycles of coronary artery occlusion, rapid ventricular pacing, stimulation of adenosine A(1) receptors, and administration of wall fragments of Gram-negative bacteria, such as lipopolysaccharide (LPS). The aim of this study was to investigate whether lipoteichoic acid (LTA), a cell wall fragment of Gram-positive bacteria, can induce a SWOP in a rat model of left anterior descending coronary artery (LAD) occlusion (25 minutes) and reperfusion (2 hours). Thus, 166 male Wistar rats were pretreated (2 to 24 hours) with saline, LTA (1 mg/kg IP), or LPS (1 mg/kg IP) and subjected to LAD occlusion/reperfusion. Pretreatment with LTA or LPS for 16 hours led to a substantial, approximately 65%, reduction in infarct size and a reduction in the release of cardiac troponin T into the plasma. The dose of LTA used had no toxic effect (on any of the parameters studied), whereas the same dose of LPS caused a time-dependent activation of the coagulation system and liver injury. By use of RNase protection assays, it was determined that LPS caused a time-dependent induction of tumor necrosis factor-alpha, interleukin-1beta, and manganese superoxide dismutase mRNA content in the heart, whereas LTA failed to induce manganese superoxide dismutase. LPS also caused an upregulation of the expression of intercellular adhesion molecule-1 and P-selectin, whereas LTA downregulated these molecules and attenuated the accumulation of polymorphonuclear granulocytes caused by myocardial ischemia/reperfusion. This study demonstrates for the first time that pretreatment with LTA at 8 to 24 hours before myocardial ischemia significantly reduces (1) infarct size, (2) cardiac troponin T, and (3) the histological signs of tissue injury in rats subjected to LAD occlusion and reperfusion. The mechanism(s) underlying the observed cardioprotective effects of LTA warrants further investigation but is likely to be related to its ability to inhibit the interactions between the coronary vascular endothelium and polymorphonuclear granulocytes. Therefore, LTA represents a novel and promising agent capable of enhancing myocardial tolerance to ischemia/reperfusion injury.
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PMID:Lipoteichoic acid induces delayed protection in the rat heart: A comparison with endotoxin. 1084 67

-CD36 is 1 of the class B scavenger receptor expressed on monocytes, monocyte-derived macrophages (Mphi), platelets, and adipocytes. In our previous studies, we reported that the uptake of oxidized low density lipoproteins (OxLDLs) is reduced by approximately 50% in Mphi from CD36-deficient patients compared with that in control subjects. Recently, we have shown that CD36 is highly expressed in human atherosclerotic aorta. Possibilities have been raised that besides the wide distribution and multifunctional characteristics of CD36, this molecule may also be involved in the mediation of intracellular signaling. The aim of the present study was to elucidate the role of CD36 in cytokine secretion and to investigate the CD36-mediated intracellular signaling stimulated by OxLDL. On addition of OxLDL or thrombospondin-1, the Mphi from CD36-deficient patients secreted significantly less amounts of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) compared with those from controls. RNase protection assay with multiprobe template sets demonstrated that after incubation with OxLDL, the mRNAs of a variety of cytokines, including genes encoding IL-1Ra, IL-1beta, IL-6, TNF-alpha and -beta, and interferon (IFN)-gamma and -beta, were significantly lower in the Mphi of patients. The addition of antibody against CD36 attenuated this OxLDL-induced response in controls. We also observed a reduced response in nuclear factor-kappa B (NF-kappa B) activity in OxLDL-stimulated Mphi from CD36-deficient patients. Unlike OxLDL, stimulation by lipopolysaccharide induced an increase in NF-kappa B activity in Mphi from CD36-deficient patients, suggesting that lipopolysaccharide-mediated signaling was conserved. These results demonstrate that in addition to the reduced OxLDL uptake that we reported previously, CD36-deficient patients may also have an impaired response of OxLDL-induced NF-kappa B activation and subsequent cytokine expression.
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PMID:Oxidized LDL-induced NF-kappa B activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients. 1093 17

Serotonin (5-HT) up-regulates B and T lymphocyte proliferation by activating mitogen-induced cell surface 5-HT(1A) receptors. The mechanism of 5-HT(1A) receptor induction by B and T cell mitogens at the mRNA and protein levels in mouse splenocytes was addressed. Quantitation by RNase protection assay showed maximal increases of 3.4-, 3.0-, 3.8-, and 4.9-fold in relative 5-HT(1A) mRNA levels after 48 h of stimulation of splenocytes with lipopolysaccharide, phytohemagglutinin, concanavalin A, or phorbol 12-myristate 13-acetate plus ionomycin, respectively, as compared with unstimulated cells. Mitogens did not alter 5-HT(1A) mRNA stability (t(12) = 26 h), but induction of 5-HT(1A) mRNA was blocked by the transcriptional inhibitor actinomycin D (10 microgram/ml) and by inhibition of nuclear factor-kappaB signaling. Additionally, mitogenic stimulation of transcription was paralleled by increased cell surface 5-HT(1A) receptor immunoreactivity in splenocytes. Thus, mitogen-induced 5-HT(1A) receptor expression appears to involve transcriptional regulation by the nuclear factor-kappaB signaling cascade. Increased expression of the 5-HT(1A) receptor in activated B and T lymphocytes may enhance the immune response and provide therapeutic target for tissue inflammation and immune stimulation.
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PMID:Transcriptional mechanisms for induction of 5-HT1A receptor mRNA and protein in activated B and T lymphocytes. 1108 Apr 94

Congenic strains of mice which differ only in their H2 haplotype were used to examine the effects of MHC genes on production of pro-inflammatory cytokines, as we have shown previously that H2(b) mice produce low levels of T cell cytokines compared to congenic H2(k) and H2(d) mice. RNase protection assays were used to assess cytokine mRNA and cytokine protein was assessed by ELISA or bioassay. Concanavalin A or phorbol myristate acetate/calcium ionophore/anti-CD3 stimulation of spleen cells from H2(b) congenic mice induced less IL-1, IL-2, IFN-gamma and MIF mRNA and/or protein than the equivalent cells from H2(d) mice. However, following stimulation with lipopolysaccharide or phorbol myristate acetate/calcium ionophore, peritoneal cells from H2(b) mice synthesised significantly more IL-1 beta, TNF-alpha, TNFR and IFN-gamma protein and IFN-gamma mRNA than cells from congenic H2(k) or H2(d) mice. These differences were evident in congenic C57BL/10 and/or BALB/c strains. We suggest that the low IL-1 production in H2(b) spleen cultures is secondary to lower T cell activation. Evidence that the H2(b) haplotype carries an immunoregulatory allele which affects cytokine production warrants further investigation.
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PMID:The H2(b) haplotype modifies the production of pro-inflammatory cytokines: implications for immunopathology. 1112 8


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