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)

Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-alpha production. Using compounds of two distinct chemical structural classes, a quinazolinedione (CP-77059) and a 4 arylpyrrolidinone (rolipram), we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-alpha production in vitro in sodium periodate-elicited murine macrophages (IC50s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-alpha induced by a sublethal LPS injection; (ii) LPS-induced endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublethal (5 micrograms/mouse) injection of LPS, serum TNF-alpha levels in mice peaked sharply, reaching concentrations of 3-12 ng/ml 90 min after injection. In this sublethal LPS assay, CP-77059 was about 30 times more potent than rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro IC50s for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum TNF-alpha levels, and also inhibited mortality 66%. In the LPS/galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with galactosamine, only 0.1 microgram of LPS/mouse is necessary for serum TNF-alpha elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-alpha and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-alpha response (without a serum TNF-alpha elevation), rolipram significantly inhibited paw swelling as well as localized TNF-alpha levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-alpha elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-alpha production and inflammatory responses in murine systems.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. 769 10

Effects of (1-->3)-beta-D-glucans on tumor necrosis factor-alpha (TNF-alpha) production in mice in vivo were investigated with or without triggering stimulation of lipopolysaccharide (LPS). Administration of grifolan (GRN) (100-250 micrograms/mouse) obtained from Grifola frondosa, did not elevate the TNF-alpha concentration in serum, but significantly elevated LPS (10 micrograms/mouse)-elicited TNF-alpha production in serum. The priming effect was observed as early as 2 h after administration and remained high for 3 weeks. The priming effect was dependent on the strain of mice, i.e. ICR, BALB/c, and MRL/lpr (15 weeks old) showed high response. In addition, GRN administration increased membrane-bound TNF-alpha assessed by Western blotting and flow cytometry. Comparing the activity using structurally related glucans obtained from other microorganisms, highly branched glucans, SSG isolated from Sclerotinia sclerotiorum IFO 9395 and OL-2 from Omphalia lapidescence significantly increased TNF-alpha production. Small molecular weight GRN derivatives prepared by heat degradation method showed weaker priming effect. These facts suggested that the glucans showed priming effect of TNF-alpha production in vivo and that this effect was related to the degree of branching and molecular weight.
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PMID:Enhancement of LPS triggered TNF-alpha (tumor necrosis factor-alpha) production by (1-->3)-beta-D-glucans in mice. 773 26

Cytokine production was measured in mice during Salmonella typhimurium sepsis and intoxication. In mice given live S. typhimurium (10 cfu/mouse), by intra-peritoneal injection, serum levels of tumour necrosis factor (TNF)-alpha and interleukin-6 increased steadily from day 1 until day 4. Interferon-gamma levels showed a transient peak on day 3. Interleukin-1-alpha levels were very low. There were high bacterial counts in the livers at day 3 and deaths occurred from day 4 onwards. Intraperitoneal injection of lipopolysaccharide or heat-killed bacteria also induced all of the cytokines, but their time of appearance and levels varied greatly. Cytokine induction by heat-killed bacteria was more marked. Endotoxaemia decreased with time during intoxication and increased during sepsis. Bioactive TNF, as measured by a cytotoxicity assay, was found only in mice given heat-killed bacteria.
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PMID:Cytokine stimulation during Salmonella typhimurium sepsis in Itys mice. 775 14

Comparison of cytokine stimulation by lipopolysaccharide (LPS) of Bacteroides fragilis and Salmonella typhimurium was done to study the early events occurring in vivo. Mice injected intraperitoneally with either LPS demonstrated endogenous production of all the cytokines studied (tumor necrosis factor-alpha, interferon-gamma and interleukin-6) within 6 hr in the bloodstream. However induction of all the cytokines by B. fragilis LPS (50 micrograms/mouse) was much weaker compared with S. typhimurium LPS (50 micrograms/mouse). Even a dose of S. typhimurium LPS 40 times smaller (1.2 micrograms/mouse) induced cytokines more strongly compared with B. fragilis LPS. Thus, a weak biological response to B. fragilis LPS as evidenced by chick embryo lethality, limulus lysate gelation, LD50 for mice and rabbit pyrogenicity could be due to weak induction of bioactive mediators by LPS.
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PMID:Comparison of cytokine induction by lipopolysaccharide of Bacteroides fragilis with Salmonella typhimurium in mice. 785 18

The reverse transcription polymerase chain reaction (RT-PCR) was used to assess the induction of mRNA of the proinflammatory cytokines IL-1 beta, IL-6 and TNF alpha in the spleen, pituitary, hypothalamus and hippocampus of mice after an intraperitoneal injection of lipopolysaccharide (LPS, 10 micrograms/mouse). The kinetics of cytokine gene expression induced by peripheral LPS in the pituitary and brain structures were different from that observed in the spleen. For IL-1 beta the dose-response curve was also measured and also found to be different. These results support the idea that one pathway by which peripheral immune stimuli affect brain functions includes local synthesis of proinflammatory cytokines in certain brain structures.
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PMID:Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. 787 46

Human peritoneal macrophages were collected from dialysis bags of renal patients on Continuous Ambulatory Peritoneal Dialysis (CAPD), during an inflammation-free period. The macrophage suspension was cultured in presence of bacterial lipopolysaccharide (LPS) and phorbol myristate acetate (TPA). The cultured macrophages were tested for therapeutic effectiveness against a human tumor-cell line, RC43, implanted subcutaneously in NMRI nude mice. The macrophages were injected around the tumor starting from the 14th day after inoculation, when the tumor growth was already detectable (mean tumor size 7 mm). Three injections of macrophages on days 14, 18 and 21 induced hemorrhagic patches at the tumor site and almost complete regression of the tumor. One injection of macrophages cultured either in presence of LPS+TPA or of LPS+TPA+PGE2 resulted in marked slow-down of the tumor growth. Injection of either TNF-alpha (4000 U/mouse) or PGE2 (150 ng/mouse) given at the site of the palpable small tumor had no effect. Macrophages cultured in medium or in medium supplied with either TPA, LPS or TPA+LPS, were not effective in nude mice bearing large (16 to 19 mm) tumors. The results obtained suggest that activated human macrophages might be therapeutically effective at certain stages of human cancer.
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PMID:Therapeutical effect of activated human macrophages on a human tumor line growing in nude mice. 792 26

We measured iodine-125-labeled recombinant human interleukin-1 alpha (125I-IL-1 alpha) binding in the hippocampus, pituitary, liver, spleen and testis, and plasma adrenocorticotropic hormone (ACTH) and corticosterone levels after i.p. injection of various dose and treatment regimens of the bacterial endotoxin, lipopolysaccharide (LPS). Plasma ACTH and corticosterone levels were significantly increased at 2 h after acute administration of LPS (60 or 300 micrograms/mouse). 125I-IL-1 alpha binding in all peripheral tissues examined was significantly and comparably decreased at 2 h after a single injection of 30 micrograms or 300 micrograms LPS/mouse. On the other hand, 125I-IL-1 alpha binding in hippocampus was significantly decreased only after high dose administration of LPS (300 micrograms/mouse). In order to evaluate if activation of IL-1 in brain resulting in the observed decrease in 125I-IL-1 alpha binding may require more sustained exposure to endotoxin, we compared the effects of a single injection (60 micrograms/mouse) and two injections of LPS (30 micrograms/mouse each at 0 and 12 h). A single injection of LPS (60 micrograms/mouse) decreased 125I-IL-1 alpha binding in the testis but not in the hippocampus, while two LPS injections (30 micrograms/mouse each at 0 and 12 h) caused dramatic reductions in 125I-IL-1 alpha binding in both the hippocampus and testis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of interleukin-1 receptors and hypothalamic-pituitary-adrenal axis by lipopolysaccharide treatment in the mouse. 795 41

Millions of people have been exposed to silicones because of the widespread use in consumer products such as cosmetics and toiletries, food products, household products and paints. Silicones have wide use in medical practice, including lubricants in tubing and syringes, and as implantable devices. The most prevalent silicone in medical use is polydimethylsiloxane. This study was undertaken to determine the subchronic immunotoxicologic potential of the principal constituents of breast implants: silicone fluid, silicone gel and silicone elastomer. An alternative covering for devices containing silicone gels, polyurethane, was also included in the study. Silicone fluid and gel were injected subcutaneously into female B6C3F1 mice (1 ml/mouse) and 6 mm disks of silicone elastomer or polyurethane were implanted subcutaneously. There were no treatment-related deaths or overt signs of toxicity. None of the tested materials had notable effects on body or organ weights, erythrocytes or leukocytes in the blood, blood chemistries such as alanine aminotransferase, urea nitrogen, glucose, albumin or total protein. The cellularity of the bone marrow and responses to CSF-GM and CSF-M were normal. The tested silicones did not alter the distribution of B cells and T cells in the spleen, but polyurethane perturbed the distribution of CD4+CD8+ and CD4-CD8- T cells. The antibody response to sheep erythrocytes was not markedly altered, nor were proliferative responses to concanavalin A, phytohemagglutinin, lipopolysaccharide or allogeneic cells. Reticuloendothelial function was normal, but polyurethane evoked an enhanced phagocytosis of Covaspheres by adherent peritoneal cells. Natural killer cell activity and serum complement were not altered. All silicone materials afforded modest protection to a challenge with Listeria monocytogenes that killed 40 to 58% of control mice. Host resistance to Streptococcus pneumoniae or the B16F10 tumor was not affected by any of the treatments. There is a pattern indicative of some perturbation of T cell differentiation in mice implanted with a polyurethane disk.
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PMID:Subchronic 10 day immunotoxicity of polydimethylsiloxane (silicone) fluid, gel and elastomer and polyurethane disks in female B6C3F1 mice. 798 83

Millions of people have been exposed to silicones which are present in consumer goods such as cosmetics and toiletries, processed foods and household products. In addition, silicones have been used extensively in medical practice as a lubricant in tubing and syringes, and as implantable devices. A silicone widely used in medical practice is polydimethylsiloxane. This study was undertaken to determine the immunotoxicologic potential of long term exposure to the principal constituents of breast implants: silicone fluid, silicone gel and silicone elastomer. An alternative covering for devices containing silicone gels, polyurethane, was also included in the study. Silicone fluid and gel were injected subcutaneously into female B6C3F1 mice (1 ml/mouse) and 6 mm disks of silicone elastomer or polyurethane were implanted subcutaneously. There were no treatment-related deaths or overt signs of toxicity during the 180 day exposure. None of the tested materials had notable effects on body or organ weights, erythrocytes or leukocytes in the blood, blood chemistries such as alanine aminotransferase, urea nitrogen, glucose, albumin or total protein, or serum CH 50 or C3 levels. The cellularity of the bone marrow and responses to CSF-GM and CSF-M were normal. The tested silicones and polyurethane marginally reduced the level of Ig+ cells in the spleen but did not consistently alter the distribution of T cell surface markers. The antibody response to sheep erythrocytes was not markedly altered, nor were proliferative responses to concanavalin A, phytohemagglutinin, lipopolysaccharide or allogeneic cells. Reticuloendothelial function was normal, as was phagocytosis of chicken erythrocytes and Covaspheres by adherent peritoneal cells. Natural killer cell activity was depressed in all silicone treatment groups and in mice implanted with polyurethane. No silicone or polyurethane treatment group displayed altered susceptibility to a challenge with Listeria monocytogenes, Streptococcus pneumoniae or the B16F10 tumor. The only consistent effect of 180 day exposure to silicone materials or polyurethane was a modest depression of natural killer cell activity.
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PMID:Immunotoxicity of 180 day exposure to polydimethylsiloxane (silicone) fluid, gel and elastomer and polyurethane disks in female B6C3F1 mice. 798 84

To study the mechanism of synergism between Bacteroides fragilis and Escherichia coli, the effect of sublethal dose of E. coli lipopolysaccharide (LPS) (25 micrograms/mouse) was checked on B. fragilis abscess formation. LPS was administered prior or after inoculum injection. No significant difference in the abscess size was observed at necropsy on day 6. However, all the groups receiving LPS showed higher incidence of recovery of additional intestinal bacteria (23.5-45.5%) from the abscess pus. When LPS was given 4 hr prior to inoculum administration, 83-100% mortality was observed. Detailed investigation showed autoclaved cecal contents alone could also cause similar mortality. Studies with stimulation of endogenous cytokines by E. coli LPS demonstrated induction of all of them within 3 hr in the blood stream with TNF-alpha demonstrating peak at 1 hr, IL-1 alpha and IL-6 at 4 hr and IFN-gamma between 6-9 hr with moderately high levels at 4 hr. This E. coli LPS-triggered cytokine cascade possibly gets further stimulated by injection of autoclaved cecal contents containing high concentration of endotoxins (1.6 x 10(5) EU/ml) contributed by dead bacteria and lead to the mortality of animals.
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PMID:Effect of Escherichia coli lipopolysaccharide on Bacteroides fragilis abscess formation and mortality in mice. 804 6


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