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)

The mode of pathogenic action of the Steptococcus pyogenes superantigen erythrogenic toxin type A (ETA) in causing toxic shock-like syndrome in humans is thought to be mediated by massive release of cytokines by patients immune cells. The cytokine-inducing capacity of ETA as an extracellular protein was compared with that of lipopolysaccharide (LPS), a component of cell wall of gram-negative bacteria. Peritoneal macrophages and splenocytes of BALB/c and C3H/HeJ mice were stimulated by ETA and LPS. Tumor necrosis factor (TNF), interleukin 3 (IL-3) and interleukin 6 (IL-6) activities in the supernatants of stimulated cells were evaluated. In contrast to LPS, ETA induced only low amounts of IL-6 and no detectable TNF activities in peritoneal macrophage supernatants. ETA-triggered BALB/c and C3H/HeJ splenocytes produced great amounts of IL-6. ETA triggered the production of IL-3 by both mice strains splenocytes in a dose dependent manner. The amounts of IL-3 in supernatants were comparable to those induced by concanavalin A. The simultaneous presence of ETA and LPS in macrophage and splenocyte cultures induced a slight enhancement above an additive value after 72-96 h. Challenge of BALB/c mice with ETA 6 h before the harvest of peritoneal macrophages led to an enhanced production of IL-6 upon stimulation with ETA as well as with LPS. Splenocytes of nude BALB/c mice did not produce IL-6 upon stimulation with ETA, whereas LPS-induced IL-6 production was similar in these mice and in their littermates. The pathogenic effect of ETA on host's immune cells could most likely be explained as a consequence of T cell activation. The results confirm also that LPS- and ETA-induced shock is mediated by different cell types.
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PMID:Cytokine production by murine cells activated by erythrogenic toxin type A superantigen of Streptococcus pyogenes. 128 82

Human liver manganese superoxide dismutase (Mn-SOD) was highly purified by a simple procedure and crystallized. A monoclonal antibody against Mn-SOD, whose antigen-binding epitope is a C-terminus peptide was developed. Using this antibody, an enzyme-linked immunosorbent assay (ELISA) was developed. We found that Mn-SOD is highly expressed in human ovarian cancer and the serum level of the enzyme is a useful marker for the diagnosis and monitoring of the epithelial type of ovarian cancer. Tumor necrosis factor-alpha (TNF), lipopolysaccharide, IL-1 and phorbol ester induced the m-RNA of Mn-SOD as well as protein levels in TNF-resistant cells. No such induction was observed in Cu, Zn-SOD. Studies on the induction mechanisms indicated that at least two separate signal-transducing pathways are involved in expression of the Mn-SOD gene. One is triggered by protein kinase C activation itself in the absence of new protein synthesis. The other can be activated by stimulations with various cytokines in which a protein factor that can be induced by phorbol ester treatments is involved.
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PMID:Expression of Mn-superoxide dismutase in carcinogenesis. 130 94

Tumor necrosis factor (TNF) is a pleiotropic biomodulator and an important inducer of certain pathophysiologic immune reactions such as granuloma formation, cachexia, and septic shock. The production of TNF by astrocytes, which may figure prominently in the development of immune responses within the central nervous system, is subject to post-transcriptional regulation. We have previously shown that in virus-stimulated astrocytes, inhibition of protein kinase C results in a specific, 10-fold decrease in TNF mRNA half-life. Here we show that the decay of TNF messages induced in the macrophage-like cell line RAW 264.7 by either virus or lipopolysaccharide was subject to similar regulation, and that this pathway influenced the amount of TNF protein released by stimulated cells. Using a modified RNase protection assay, we demonstrate that inhibition of protein kinase C significantly enhanced the rate of poly(A) removal from TNF mRNA, thus facilitating an early event in the process of mRNA degradation.
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PMID:Poly(A) removal is the kinase-regulated step in tumor necrosis factor mRNA decay. 131 Mar 8

Activation of expression of genes encoding transcription factors: c-fos and c-jun and formation of AP1 transcriptional complex in human monocytes was investigated. It was found that lipopolysaccharide induced strongly both c-fos and c-jun expression as well as AP1 formation. Interferon gamma activated strongly c-fos and weakly c-jun and AP1. Tumor necrosis factor induced slightly c-fos and had almost no effect on c-jun and AP1. The data suggest that differences in functional responses elicited in monocytes by all three factors may be dependent on different routes on nuclear signalling employed by the factors.
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PMID:Transcription factor activation and functional stimulation of human monocytes. 131 39

Tumor necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6) are central mediators of the inflammatory response. We investigated the modulation of these cytokines by hormones in vitro. Murine adherent peritoneal exudate cells (PEC) were exposed to various concentrations of hormones followed by lipopolysaccharide (LPS, 10 micrograms/ml). TNF, IL-1 and IL-6 production were assessed by bioassays, enzyme-linked immunosorbent assays (ELISA) or Western blot, and specific RNA transcripts by Northern blot. Hydrocortisone in concentrations as low as 10 ng/ml had dramatic inhibitory effects on supernatant levels of TNF and IL-1 and on TNF, IL-1 and IL-6 transcript number. Supernatant levels of IL-6 were only slightly diminished by hydrocortisone. Adrenocorticotrophic hormone (ACTH) and insulin increased supernatant levels of TNF bioactivity in response to LPS, while each decreased available TNF-alpha gene transcripts. Thus TNF protein production was affected at a post-transcriptional level. ACTH and insulin increased supernatant levels of IL-6 produced in response to LPS without altering available transcripts. Corticotrophin-releasing factor (CRF), epinephrine and glucagon had no effect on supernatant levels of cytokine. Thus, physiological and pharmacological concentrations of hydrocortisone had dramatic inhibitory effects on the supernatant levels of TNF and IL-1, and on the number of available TNF, IL-1 and IL-6 transcripts in PEC exposed to LPS, but had minimal effects on supernatant levels of IL-6 bioactivity. This hydrocortisone action may be a specific negative feedback system for IL-1 and TNF, with relative sparing of IL-6.
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PMID:Hormonal regulation of inflammatory cell cytokine transcript and bioactivity production in response to endotoxin. 131 63

Tumor necrosis factor-alpha (TNF) is a cytokine released by mononuclear cells in response to inflammation and sepsis. Since the biological effects of TNF are consistent with the systemic and intestinal features of ulcerative colitis, the role of TNF was examined in a rabbit model of chronic colitis. Peripheral blood mononuclear cells were isolated, stimulated with lipopolysaccharide, and cultured supernatants assayed for TNF levels using a cytotoxic assay on mouse fibrosarcoma L929 cells. Basal levels of TNF production by mononuclear cells from 13 normal rabbits (124.3 units/ml +/- 27.1 units/ml, mean +/- SE) were not different from nine rabbits with colitis (83.6 units/ml +/- 24.4 units/ml, P > 0.05). Treatment with lipopolysaccharide (100 micrograms/ml) induced increased TNF production by mononuclear cells isolated from both normals (672.0 units/ml +/- 197.5 units/ml, P < 0.05) and rabbits with colitis (1114.0 units/ml +/- 489.6 units/ml, P < 0.05). However, at all lipopolysaccharide concentrations stimulated TNF levels were comparable in experimental and control groups (P > 0.05). In light of the role of leukotrienes in inflammation, a separate group of rabbits with colitis was investigated following treatment with an oral leukotriene B4 receptor antagonist. Serum TNF levels in 15 control rabbits (32.5 units/ml +/- 7.6 units/ml, mean +/- SE) were not significantly different from rabbits with colitis receiving either leukotriene B4 receptor antagonist (35.7 units/ml +/- 9.2 units/ml, N = 13) or vehicle alone (50.3 units/ml +/- 10.2 units/ml, N = 14) (ANOVA, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Systemic tumor necrosis factor-alpha production in experimental colitis. 133 Apr 61

Tumor necrosis factor-alpha (TNF-alpha) production by unstimulated and lipopolysaccharide (LPS)-stimulated peripheral monocytes has been studied in 17 acute myeloid leukemia (AML) patients, 54 AML patients in complete remission (AML-CR), 9 acute lymphoblastic leukemia (ALL) patients and 13 ALL patients in complete remission (ALL-CR). TNF-alpha production by the unstimulated monocytes in ALL patients (n = 6, mean: 6.6 +/- 4.9 u/ml) was higher than that of normal controls (n = 13, 0.9 +/- 0.7 u/ml), AML patients (n = 14, 2.0 +/- 2.1 u/ml) and AML-CR patients (n = 21, 1.4 +/- 1.2 u/ml). TNF-alpha production by the LPS-stimulated monocytes of the AML-CR patients (n = 54, 12.4 +/- 13.4 u/ml) was significantly higher than that of the normal controls (n = 21, 3.5 +/- 2.5 u/ml) and the AML patients (n = 17, 2.6 +/- 2.4 u/ml), p < 0.01, but there were not any significant differences among the AML-CR patients and the ALL patients or the ALL-CR patients. We separated the AML-CR patients into 3 groups, depending on the length of their remission, and found that AML-CR patients with longer than 6 months (M) but less than 60 M (n = 21, 15.7 +/- 16.9 u/ml) and the patients with a remission longer than 60 M (n = 11, 18.2 +/- 15.9 u/ml) had significantly higher TNF-alpha production than that of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The monocyte tumor necrosis factor-alpha production in patients with acute leukemia in complete remission. 134 64

Tumor necrosis factor (TNF), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. A stable prostacyclin analogue (iloprost) was investigated for its ability to interfere with TNF secretion of lipopolysaccharide (LPS)-stimulated macrophages. It could be demonstrated by bioassays that LPS-induced TNF production was suppressed in a dose-dependent manner when macrophages were treated with iloprost at the time of LPS stimulation. Northern blot analysis revealed that iloprost inhibited TNF production at the transcription level. In vivo, endotoxin-induced mortality rates in galactosamine-sensitized mice could be significantly (P less than .05) reduced by iloprost administration. It is assumed that prostacyclin modulates endotoxin-induced and TNF-mediated inflammation in septic shock.
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PMID:Inhibition of endotoxin-induced macrophage tumor necrosis factor expression by a prostacyclin analogue and its beneficial effect in experimental lipopolysaccharide intoxication. 137 36

Tumor necrosis factor-alpha (TNF-alpha), a mononuclear phagocyte-derived peptide is known to participate in the pathogenesis of fever. To determine whether a feedback mechanism exists by which elevated temperatures influence TNF-alpha generation, we have examined the effects of heat shock on the in vitro synthesis of TNF-alpha by rat glomeruli, inflammatory peritoneal macrophages and blood monocytes. Preexposure of peritoneal macrophages to elevated temperatures for 20 min decreased the subsequent lipopolysaccharide-induced release of TNF-alpha bioactivity. The mean reductions were 11.9 +/- 5.0%, 86.3 +/- 12.0%, and 95.2 +/- 3.5% after pretreatment at 39, 41 and 43 degrees C, respectively. Reductions, that were transient, were maximum when lipopolysaccharide was added 0-2 h after heat shock. They correlated with the decreased release of immunoreactive TNF-alpha and the decreased expression of both cell-associated TNF-alpha molecule and TNF-alpha mRNA. Heat shock-induced inhibition of TNF-alpha release was independent of variations of prostaglandin synthesis, but was possibly related to the induction of heat-shock proteins since (a) macrophages exposed to heat shock synthesized the major 70- and 90-kDa heat-shock proteins, and (b) chemical inducers of the heat-shock response were also effective inhibitors of TNF-alpha release. The mean reduction of TNF-alpha release after pretreatment at 41 degrees C was found to be identical in glomerular tissue (82.0 +/- 7.5%), but significantly less in blood monocytes (43.9 +/- 10.9%). This supports the hypothesis that a negative-feedback mechanism exists between elevated temperature and lipopolysaccharide-induced TNF-alpha synthesis, and suggests that this regulation is less active in blood monocytes than in tissue macrophages.
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PMID:Heat shock prevents lipopolysaccharide-induced tumor necrosis factor-alpha synthesis by rat mononuclear phagocytes. 142 22

Endotoxins, the lipopolysaccharide (LPS) moieties on the bacterial cell wall, cause many of the pathological features of Gram-negative septicemia. Tumor necrosis factor (TNF), primarily a product of monocyte/macrophages, has been shown to mediate many of the pathophysiological effects of endotoxin. Kupffer cells, the largest macrophage population in the body, release TNF when stimulated by LPS in vitro. A recombinant human hybrid interferon-alpha A/D (rIFN-alpha) markedly inhibited this LPS-elicited TNF production by Kupffer cells. The effects of rIFN-alpha were further tested in C57BL/6 mice receiving a lethal dose (400 micrograms/mouse) of LPS. All LPS-treated mice died within 2 days. Pretreatment with rIFN-alpha 1 h before LPS challenge improved the survival at 3 days to 22% (5/23, p < 0.04). In contrast, rIFN-alpha was more effective when administered 20 min after LPS injection, increasing the survival rate to 81% (13/16, p < 0.0001). TNF mRNA expression in the liver and spleen 50 min after LPS challenge, and plasma TNF 1.5 h after LPS were also reduced by either pretreatment or post-treatment with rIFN-alpha. Subsequently, experiments were carried out to test the efficacy of delayed rIFN-alpha treatment. A significant protective effect was still apparent when rIFN-alpha was administered 6, 10 and even 14 h (81%, 62% and 28% survival, respectively) after LPS challenge when serum TNF levels had already returned to near baseline. These experimental results suggest that rIFN-alpha might have a therapeutic potential for the prevention and treatment of the deleterious effects associated with endotoxemia besides mechanisms initially blocking TNF production.
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PMID:Interferon-alpha prevents endotoxin-induced mortality in mice. 144 3


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