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)

Dexamethasone inhibits lipopolysaccharide-induced synthesis of the cytokine, interleukin-1 beta, in cerebrospinal fluid of patients with bacterial meningitis. Along with monocytes, astrocytes are capable of producing lipopolysaccharide-induced interleukin-1 beta in the central nervous system. The objective of this study was to investigate the induction of interleukin-1 beta mRNA by lipopolysaccharide, and the inhibition of this process by dexamethasone, in human astrocytes using the astrocytoma cell line U-373MG as a model system. Dexamethasone-mediated inhibition of induction of interleukin-1 beta mRNA by lipopolysaccharide required a functional glucocorticoid receptor. In contrast to monocytes, lipopolysaccharide induction of interleukin-1 beta mRNA in U-373MG cells required de novo protein synthesis. Dexamethasone also had no effect on lipopolysaccharide-induced interleukin-1 beta transcriptional initiation in U-373MG cells. U-373MG cells were similar to monocytes, however, with respect to the ability of dexamethasone to decrease interleukin-1 beta mRNA half-life. These findings demonstrate that the mode of lipopolysaccharide induction of interleukin-1 beta mRNA, and inhibition of this process by dexamethasone, can vary in different cell types.
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PMID:Protein synthesis-dependent induction of interleukin-1 beta by lipopolysaccharide is inhibited by dexamethasone via mRNA destabilization in human astroglial cells. 759 67

Chronic loss of adrenocorticosteroid activity by adrenalectomy (10 days) or acute inhibition of glucocorticoid receptor function by injection of an anti-progestin (RU-38486) increased sensitivity to lipopolysaccharide about 200-fold, compared to that of control animals. Daily subcutaneous injection of a mixture of the natural glucocorticoid corticosterone and the mineralocorticoid deoxycorticosterone did not restore resistance to the endotoxin. The largest dose of steroid, 400 micrograms corticosterone + 200 micrograms deoxycorticosterone, provided only partial protection against 20 micrograms LPS, which was 10% of the LD50 for animals with adrenals. The mechanisms involved in lack of effectiveness of natural corticosteroids will require further experimentation.
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PMID:Natural adrenocorticosteroids do not restore resistance to endotoxin in the adrenalectomized mouse. 826 45

alpha 1-Acid glycoprotein (AGP) is a major acute phase protein synthesized primarily by the liver. The AGP gene is transcriptionally activated in hepatocytes during the acute phase response to bacterial lipopolysaccharide. In this study, we analyzed an acute phase responsive element (APRE) located between nucleotide residues -127 to -104 relative to the transcription initiation site of the mouse AGP gene. Binding studies show that several trans-acting factors interact with the APRE. Using monospecific antibodies we demonstrate that three isoforms of the CCAAT/enhancer-binding protein (C/EBP) family, namely C/EBP alpha, C/EBP beta, and C/EBP delta, bind to the APRE. Furthermore, with liver nuclear protein from control animals, C/EPB alpha is the predominant form that binds to the APRE, whereas with nuclear proteins from acute phase-induced animals, C/EBP alpha is replaced by C/EBP beta. The mechanism of activation of the AGP gene during the acute phase response appears to involve an exchange of C/EBP alpha by C/EBP beta. C/EBP delta does not play a role in this reaction. Interestingly, the C/EBP binding site of the APRE partially overlaps a functional glucocorticoid responsive element. We present evidence that both purified C/EBP alpha and glucocorticoid receptor bind strongly to the APRE. By site-specific mutation, we have identified the C/EBP and glucocorticoid receptor binding sites in the APRE. These mutants were used in expression vectors to demonstrate that both C/EBP and glucocorticoid receptor are essential for maximal response to interleukin-6 and dexamethasone. These results demonstrate that the APRE is a composite binding site for multiple factors that are responsible for the transcriptional control of the mouse AGP. Finally, functional analyses indicate that C/EBP alpha, C/EBP beta, and C/EBP delta are strong transcriptional trans-activators of the AGP APRE in hepatoma cells. These data suggest that the regulatory activity of the C/EBP with the APRE in the liver may require interactions with adjacent proteins.
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PMID:trans-activation of the alpha 1-acid glycoprotein gene acute phase responsive element by multiple isoforms of C/EBP and glucocorticoid receptor. 834 Mar 93

We have investigated the differential regulation of the mouse (Balb/c) acute phase reactants, alpha 1-acid glycoprotein and serum amyloid A by heavy metals (Hg, Cd, Pb, Cu, Ni and Zn). Mice have two distinct alpha 1-acid glycoprotein mRNAs encoded by alpha 1-acid glycoprotein gene-1, (AGP-1) and alpha 1-acid glycoprotein gene-2 (AGP-2) and 3 distinct serum amyloid A mRNAs encoded by serum amyloid A gene-1, (SAA-1), serum amyloid A gene-2 (SAA-2) and serum amyloid A gene-3 (SAA-3). Using specific oligonucleotides as probes we have demonstrated that the AGP-1 and AGP-2 genes, and the SAA-1 and SAA-2 genes are differentially induced by heavy metals in the liver. At the peak of induction, AGP-2 mRNA is 80-100-fold higher than the AGP-1 mRNA level; the SAA-1 mRNA level is approx. 40-fold higher than SAA-2, and SAA-3 mRNA is not detected. A similar differential pattern of expression is observed in bacterial lipopolysaccharide mediated inductions. However, low levels of SAA-3 are also seen in this treatment. Adrenalectomy has no effect on the inductions by heavy metals of AGP-2 and the SAAs, indicating that the glucocorticoid receptor pathway may not function in this regulation. However, AGP-1 induction is significantly delayed, indicating that glucocorticoid may be essential for a rapid response to Hg. The liver is the major site of heavy metal induction of AGP and SAA genes; Hg induces AGP-1 and 2, and SAA-1 and 2 only in the liver. Our studies clearly show that the AGP and SAA genes belong to a subgroup of acute-phase reactants that respond to heavy metals. CRP is another member of this family. Furthermore, our data suggest that the mechanism is not directly mediated by glucocorticoid or cytokine induction pathways.
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PMID:The differential induction of alpha 1-acid glycoprotein and serum amyloid A genes by heavy metals. 835 29

The mechanisms underlying age-related impairments in febrile responses were investigated in female C57Bl/lcrf-a(t) mice. Injection of norepinephrine, to assess total thermogenic capacity, significantly increased oxygen consumption (VO2) in all age groups, although the responses of the aged mice were significantly reduced. Injection of lipopolysaccharide or murine interleukin-1 beta (mIL-1 beta) significantly increased body temperature and VO2 in the young and adult mice but not in the aged mice. The impaired responses to mIL-1 beta in the aged mice were normalized by either injection of the glucocorticoid receptor antagonist RU-38486 or by injection of an antiserum to lipocortin-1 or its purified immunoglobulin G fraction. Injection of prostaglandin E2 significantly increased VO2 and body temperature in all age groups. Resting plasma corticosterone concentrations were significantly elevated in the aged and adult mice, whereas injection of mIL-1 beta significantly raised plasma corticosterone concentrations in all animals. These findings indicate that the impaired febrile response of aged female C57Bl/lcrf-a(t) mice may be caused by increased concentrations and/or sensitivity to endogenous glucocorticoids. The impaired febrile responses of aged mice appear to be mediated by endogenous lipocortin-1.
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PMID:Impaired febrile responses of aging mice are mediated by endogenous lipocortin-1 (annexin-1). 836 99

Although plasma corticosteroid concentrations can be measured accurately, the biological effect on the target tissue is uncertain. The availability of an accurate measure of corticosteroid sensitivity would potentially clarify the putative roles of endogenous glucocorticoids in illnesses such as inflammatory disease and obesity and allow evaluation of an additional regulatory level of glucocorticoid action. To measure corticosteroid sensitivity, we developed an assay based on the inhibition by dexamethasone (Dex) of lipopolysaccharide (LPS)-induced Interleukin-6 (IL-6) production and release in whole unseparated blood in vitro. LPS induced a dose-dependent increase in IL-6 concentrations up to 34 +/- 6.6 ng/mL, reaching plateau levels after 8 h, whereas Dex dose dependently inhibited LPS-induced IL-6 production. Involvement of the glucocorticoid receptor in this response was supported by abrogation of Dex (10(-7) mol/L) inhibition of IL-6 production by the glucocorticoid receptor antagonist RU 38486. To determine whether corticosteroid sensitivity is a dynamic phenomenon, we subjected healthy males to a graded quantifiable exercise associated with increases in plasma ACTH and cortisol. Before exercise, 3 x 10(-8) mol/L Dex inhibited LPS-induced IL-6 production in vitro; after exercise, 3 x 10(-8) and 10(-7) mol/L Dex were unable to inhibit IL-6 production. We conclude that Dex suppression of LPS-induced IL-6 production is an effective means of determining corticosteroid sensitivity, and that corticosteroid sensitivity in human subjects is a dynamic, rather than a static, phenomenon.
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PMID:Changes in corticosteroid sensitivity of peripheral blood lymphocytes after strenuous exercise in humans. 855 Jul 57

Glucocorticoids, as a part of their physiological role in the control of inflammatory and immune processes, suppress the expression of interleukin-1 (IL-1) and other cytokines. Human monocyte IL-1 receptor antagonist (IL-1ra) messenger ribonucleic acid (mRNA) expression and protein secretion are inhibited by dexamethasone. We have now further studied the regulation of IL-1ra by the major physiological human glucocorticoid, cortisol. We found that cortisol incubation induced a decrease in IL-1ra mRNA expression and a significant inhibition of IL-1ra protein secretion in cell cultures of human peripheral monocytes stimulated with the bacterial endotoxin lipopolysaccharide (LPS). Oral administration of 276 mumol cortisol to normal subjects also decreased LPS-induced IL-1ra synthesis in cultured monocytes. By coincubating the monocytes with either the mineralocorticoid antagonist spironolactone or the glucocorticoid receptor antagonist RU 38486, the in vitro cortisol-induced inhibition of LPS-stimulated IL-1ra secretion was partially reversed. The mineralocorticoid aldosterone exerted a significant decrease in LPS-induced monocyte IL-1ra secretion in vitro, which was blocked by coincubation with spironolactone. In addition, the expression of mineralocorticoid receptor mRNA in human monocytes was observed by PCR of reversed transcribed RNA. Our results further indicate that corticosteroids physiologically control the IL-1/IL-1ra system during inflammatory or immune processes. Moreover, we provide evidence that, in addition to a glucocorticoid receptor-mediated effect, the mineralocorticoid receptor is involved in the inhibition of monocyte IL-1ra secretion by cortisol.
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PMID:Inhibition of lipopolysaccharide-induced monocyte interleukin-1 receptor antagonist synthesis by cortisol: involvement of the mineralocorticoid receptor. 855 Jul 97

Incubation of human A549/8 cells with human interleukin-1 beta (50 units/ml), interferon-gamma (100 units/ml), and tumor necrosis factor-alpha (10 ng/ml) (cytomix) resulted in a marked expression of the mRNA of the inducible nitric oxide synthase (NOS II). This induction was prevented by cycloheximide. Dexamethasone markedly reduced cytokine-induced NOS II mRNA concentrations; this reduction was prevented by RU 38486 (mifepristone). Pyrrolidine dithiocarbamate, an inhibitor of nuclear factor-kappa B (NF-kappa B) activation, also significantly decreased cytomix-induced NOS II mRNA levels. When A549/8 cells were transfected with a construct containing 1570-bp 5'-flanking sequence of the murine NOS II gene cloned before a reporter gene, the murine NOS II promoter was induced up to 20-fold with cytomix but not with bacterial lipopolysaccharide. Dexamethasone as well as pyrrolidine dithiocarbamate inhibited this induction. In electrophoretic mobility shift assays, nuclear protein extracts from cytomix-induced, but not from unstimulated cells, significantly slowed the migration of an oligonucleotide containing the NF-kappa B-binding site. This band shift was markedly reduced by dexamethasone. On the other hand, cytomix-induced nuclear protein content of NF-kappa B p65 and NF-kappa B p50 was not reduced by dexamethasone (as analyzed by Western blot). Dexamethasone also did not reduce cytomix-induced expression of NF-kappa B p65 mRNA or enhance the expression of NF-kappa B inhibitor mRNA. The human and murine NOS II promoters also contain consensus sequences for activating protein-1 (AP-1) binding. However, AP-1 binding activity of nuclear extracts of A549/8 cells was not enhanced by cytomix or inhibited by dexamethasone. These data suggest that the activated glucocorticoid receptor prevents (by a protein/protein interaction) the binding of transcription factor NF-kappa B, but not AP-1, to the NOS II promoter, thereby inhibiting the induction of NOS II transcription.
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PMID:Glucocorticoids inhibit the induction of nitric oxide synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-kappa B. 856 1

Repression of NFkappaB-dependent gene expression is one of the major elements of immunosuppression by glucocorticoids. Protein-protein interactions between the glucocorticoid receptor and NFkappaB have been characterized and shown to be a possible mechanism of mutual inhibition of transactivation properties. More recently, glucocorticoid-mediated induction of IkappaBalpha, an inhibitor of NFkappaB, has been described in monocytes and lymphocytes; an increase in IkappaBalpha mRNA and protein resulted in inactivation and cytosolic retention of NFkappaB. Thus, rather than the physical interaction between the glucocorticoid receptor and NFkappaB, the up-regulation of IkappaBalpha was presented as the key element in immunosuppression by glucocorticoids. In contrast, we show that the IkappaBalpha pathway is not involved in glucocorticoid-mediated inhibition of NFkappaB activity in endothelial cells. Although transcriptional activation by NFkappaB was significantly reduced in the presence of glucocorticoids, we did not detect induction of IkappaBalpha protein that could prevent nuclear translocation of NFkappaB upon stimulation with lipopolysaccharide or tumor necrosis factor alpha. Furthermore, treatment with glucocorticoids did not seem to affect the transcription rate or mRNA stability of IkappaBalpha. We therefore conclude that, although induction of IkappaBalpha expression by glucocorticoids seems to be of importance in monocytes and lymphocytes, it cannot explain inhibition of NFkappaB-dependent gene expression in endothelial cells. Our results emphasize the relevance of physical interaction between the glucocorticoid receptor and NFkappaB in endothelial cells and thus in suppression of inflammation by glucocorticoids.
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PMID:Glucocorticoid-mediated repression of NFkappaB activity in endothelial cells does not involve induction of IkappaBalpha synthesis. 870 57

Administration of bacterial lipopolysaccharide (LPS) into mice markedly induced the apoptosis of CD4+8+ thymocytes. The injection of anti-tumor necrosis factor (TNF)-alpha antibody or RU38486, a glucocorticoid receptor antagonist, into mice definitely inhibited LPS-induced apoptosis of thymocytes. Addition of the sera 1 h after injection of LPS into in vitro cultures of thymocytes caused thymocyte apoptosis. It was also prevented by either anti-TNF-alpha antibody or RU38486. Further, recombinant TNF-alpha and hydrocortisone collaborated in induction of the thymocyte apoptosis in vitro. The in vivo phenomenon of LPS-induced apoptosis of thymocytes was reproducible by the in vitro experimental system. It was therefore suggested that both TNF-alpha and glucocorticoid participate and collaborate as effector molecules in LPS-induced apoptosis of thymocytes.
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PMID:Role of tumor necrosis factor-alpha and glucocorticoid on lipopolysaccharide (LPS)-induced apoptosis of thymocytes. 874 3


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