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)

Tumor necrosis factor-alpha (TNF) is an important humoral mediator of sepsis and endotoxin-induced shock. However, Streptococcus pneumoniae, a gram-positive organism, is the most common causative agent of community-acquired pneumonia and sepsis. We hypothesized that the pathogenesis of pneumococcal pneumonia and sepsis involves pneumococcus-stimulated TNF synthesis, and we tested that hypothesis in vitro by comparing heat-killed type III and type V pneumococcus and 23-valent purified pneumococcal capsular polysaccharides with Escherichia coli and purified lipopolysaccharide (LPS) as stimuli for TNF production by the murine macrophage cell line RAW 264.7. We evaluated TNF production in response to various doses and times of exposure to these agents, as well as the effects of indomethacin on TNF production in response to these agents. Stimulation with both types of heat-killed pneumococcus resulted in TNF production in a dose-response fashion, as did stimulation with E. coli. Fewer type III pneumococci (10 bacteria/ml) were required to stimulate significant TNF secretion than either type V pneumococcus or E. coli, but the overall dose-response curves of the three bacteria were similar. The dose-response curves for pneumococcal capsular polysaccharides and LPS were very similar, although at the highest concentration pneumococcal capsular polysaccharides stimulated more TNF secretion than did LPS (469 versus 213 U/ml). The kinetics of pneumococcus-stimulated TNF secretion were identical to the kinetics of LPS-stimulated TNF secretion. In the presence of indomethacin, pneumococcus-stimulated TNF production decreased by 87.5%, as compared with pneumococcus alone. In contrast, LPS with indomethacin stimulated 19.5% more TNF than LPS alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heat-killed pneumococci and pneumococcal capsular polysaccharides stimulate tumor necrosis factor-alpha production by murine macrophages. 811 47

Monophosphoryl lipid A (MLA), derived from lipopolysaccharide (LPS) of Salmonella minnesota strain R595, induced rapid accumulation of interferon (IFN)-gamma in mice. Tumor necrosis factor (TNF)-alpha appeared to be a cofactor for IFN-gamma induction by MLA. With low doses of MLA (< 5 micrograms), IFN-gamma induction was dependent upon exogenous TNF-alpha administered either in advance of or with MLA. A 25 micrograms dose of MLA induced significant IFN-gamma accumulation in the absence of exogenous TNF-alpha. In this case, endogenous TNF-alpha appeared to be a cofactor in the response, since suppression of TNF-alpha production with dexamethasone inhibited IFN-gamma induction, and this inhibition was overcome by administration of exogenous TNF-alpha with MLA. Treatment of animals with MLA tolerized them against LPS. Tolerant animals did not produce IFN-gamma when challenged with LPS, and this tolerance was not abrogated by supplementing mice with exogenous TNF-alpha during the challenge. Although dexamethasone inhibited IFN-gamma induction by MLA, it did not inhibit tolerance induction by MLA.
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PMID:Effects of tumor necrosis factor and dexamethasone on the regulation of interferon-gamma induction by monophosphoryl lipid A. 813 45

Tumor necrosis factor (TNF), a compartmentalized cytokine, is a key mediator in the systemic inflammatory response syndrome and may play a role in multiorgan failure. To assess whether compartmentalization of alveolar TNF is preserved following lung injury, isolated perfused lungs from Sprague-Dawley rats were given intratracheally 1 ml/kg of phosphate-buffered saline (PBS), 0.1 mg/kg of lipopolysaccharide (LPS), or 125,000 units of murine recombinant TNF (mrTNF). To induce lung leak, one group of rats was given 50 mg/kg of alpha-naphthylthiourea (ANTU) intraperitoneally. Then, 125,000 units mrTNF was given intratracheally to these lungs. Samples of perfusate were assayed for TNF by the L929 cytotoxicity assay before (0 min) and 180 min after the intratracheal challenge, and bronchoalveolar lavage (BAL) was performed for TNF assay. ANTU increased lung leak but intratracheal TNF and LPS did not. The isolated perfused lung preparation expressed small amounts of perfusate TNF and underwent minimal leak that was not caused by TNF release. Endogenous or exogenous intrapulmonary TNF remained predominantly compartmentalized, but following ANTU, TNF readily appeared in the perfusate. Compartmentalization of alveolar TNF is lost during alveolar-capillary injury, suggesting that the injured lung may contribute to a systemic inflammatory response and subsequent multiorgan failure.
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PMID:Loss of compartmentalization of alveolar tumor necrosis factor after lung injury. 817 48

Tumor necrosis factor (TNF) is a pivotal mediator of endotoxin shock, but the regulation of lipopolysaccharide (LPS)-induced TNF production in different populations of mononuclear cells has not been fully clarified. Protein kinase C (PKC) is thought to play a central role in signal transduction in response to inflammatory stimuli. We studied the effect of two PKC inhibitors, staurosporine (STP) and sphingosine (SPG), on TNF production in rat alveolar macrophages (AM) and in whole blood (BM) incubated with 0.25-25,000 ng/ml of LPS. We also assessed the role of STP encapsulation into pH-sensitive and pH-insensitive liposomes composed of cholesterolhemisuccinat/dioleoylphosphatidyl ethanolamine and cholesterolhemisuccinat/distearylphosphatidyl choline, respectively. LPS induced a dose-dependent TNF response that was 2.5-4.5-times higher in AM than in BM with the same amount of monocytes. SPG and STP significantly reduced TNF in both cultures by 40-96%. Encapsulation of STP into pH-sensitive, but not pH-insensitive liposomes, significantly increased the effectiveness of TNF suppression. We conclude that the LPS-induced TNF production by AM and BM is strongly dependent on PKC activation. However, AM were less sensitive to PKC inhibition than BM.
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PMID:Protein kinase C inhibitors suppress LPS-induced TNF production in alveolar macrophages and in whole blood: the role of encapsulation into liposomes. 818 58

Human neutrophil azurophilic granules contain an approximately 55-kDa protein, known as bactericidal/permeability-increasing protein (BPI), which possesses a high-affinity binding domain for the lipid A component of lipopolysaccharide (LPS). The in vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethal Escherichia coli bacteremia. Five baboons were treated with BPI (5 mg/kg bolus injection followed by a 95 micrograms/kg/min BPI infusion over 4 hr), while four additional animals received a genetically engineered variant of BPI (NCY103). Five animals received a placebo treatment and served as controls. Both wild-type rhBPI and NCY103 significantly (P < 0.05) decreased blood levels of LPS throughout an 8-hr evaluation period following live bacterial challenge. Two hours following E. coli administration, LPS levels peaked in the controls, at 6.86 +/- 3.22 ng/ml, whereas LPS levels were 3.39 +/- 2.1 ng/ml in the BPI group and 2.04 +/- 1.18 ng/ml in the NCY103 group. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 levels likewise were attenuated in the treatment groups, whereas circulating sTNFR I was significantly (P < 0.05) reduced only in the BPI group. Leukocytopenia and granulocytopenia were significantly (P < 0.02) lessened in the BPI group, by an average of 59% leukocytopenia and 65% granulocytopenia, respectively. This study supports the concept of E. coli LPS neutralization by BPI in vivo and demonstrates that a moderate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.
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PMID:The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock. 819 14

Tumor necrosis factor-alpha (TNF alpha) is a potent cytokine believed to participate in the development of endotoxin-induced shock and the adult respiratory distress syndrome. Treatment of animals with beta-glucan prior to bacterial challenge reduces TNF alpha release and prevents death. We therefore hypothesized that beta-glucan might regulate TNF alpha secretion from macrophages in response to lipopolysaccharide (LPS). Rat alveolar macrophages were cultured in the presence of beta-glucan alone and the TNF alpha secretion quantified using an L929 cytotoxicity assay. Concentrations of beta-glucan less than 500 micrograms/ml were found to stimulate TNF alpha release from macrophages. However, concentrations of beta-glucan greater than 500 micrograms/ml resulted in suppression of the TNF alpha activity released. This reduction in TNF alpha release was not mediated by a toxic effect of beta-glucan, as large concentrations of beta-glucan had no effect on macrophage viability. We further observed that the incubation of macrophages with large concentrations of beta-glucan (500 micrograms/ml) also inhibited the secretion of TNF alpha induced by bacterial LPS. Furthermore, interferon-gamma (IFN gamma), a potent activator of TNF alpha expression, failed to overcome the inhibition of TNF alpha caused by beta-glucan. These data suggest an immunomodulatory role for beta-glucan which may explain both the TNF alpha-stimulating and -inhibiting effects of fungal beta-glucans during infection.
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PMID:Fungal beta-glucans modulate macrophage release of tumor necrosis factor-alpha in response to bacterial lipopolysaccharide. 822 3

Tumor necrosis factor-alpha (TNF alpha) is a cytokine principally secreted from macrophages and monocytes activated by agents such as lipopolysaccharide (LPS). We have recently shown that TNF alpha inhibited mouse Leydig cell steroidogenesis in vitro. LPS injection has also been shown to repress Leydig cell function and induce TNF alpha messenger RNA (mRNA) expression in testicular interstitial macrophages in vivo. A paracrine regulation of Leydig cell testosterone synthesis by testicular interstitial macrophages via TNF alpha has been proposed. To further support this possibility, we examined whether LPS can induce TNF alpha mRNA expression and protein production in testicular interstitial macrophages in vitro. The regulation of LPS-stimulated TNF alpha mRNA expression in vitro was also investigated by employing the protein synthesis inhibitor cycloheximide (CHX). TNF alpha secretion into culture supernatants was examined by both bioassay and enzyme-linked immunosorbent assay. Isolated testicular interstitial macrophages were cultured for 24 h before the initiation of treatments. Cells were treated with or without LPS (1.0 micrograms/ml) and in the presence or absence of CHX (5.0 micrograms/ml) at different time points. Northern blot analysis showed that TNF alpha mRNA was rapidly and significantly induced by LPS in testicular interstitial macrophages. The peak expression was at 2 h after the treatment, which was 8.3 +/- 2.6-fold over the control (P < 0.05). TNF alpha mRNA then declined quickly and completely disappeared by 8 h after LPS treatment. In contrast to this rapid and transient induction of TNF alpha message by LPS alone, CHX extended the induction and caused a marked increase in LPS-induced TNF alpha mRNA at 2 and 6 h. CHX induced more LPS-stimulated TNF alpha mRNA at 6 h than that at 2 h. At 3 h after LPS treatment, TNF alpha secretion was significantly stimulated (5.6 +/- 1.2 U/micrograms macrophage DNA) measured by L929 tumor fibroblast cytotoxicity. TNF alpha was also detected by enzyme-linked immunosorbent assay in culture media of testicular interstitial macrophages treated with control medium or LPS for 1, 2, and 6 h. TNF alpha secretion was increased in a time-dependent way. There are significantly higher LPS-induced TNF alpha levels in culture media at 2 h (35.4 +/- 2.2 pg/micrograms macrophage DNA) and 6 h (85.5 +/- 11.1 pg/micrograms macrophage DNA) than those in control groups. The current study demonstrates that LPS activates testicular interstitial macrophages to express TNF alpha mRNA and secrete TNF alpha protein in vitro.
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PMID:Expression, regulation, and production of tumor necrosis factor-alpha in mouse testicular interstitial macrophages in vitro. 824 79

Tumor necrosis factor (TNF) is a potent mediator of tumor cell killing by activated monocytes and macrophages. We measured TNF activity induced by muramyl peptides and lipopolysaccharide (LPS) in normal dogs. Canine adherent mononuclear cells were isolated and cultured in either medium alone or medium containing muramyl dipeptide (MDP) or MDP plus LPS. After 18 h, culture supernatants were collected and assayed for TNF activity. Sera from dogs injected with liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) were also evaluated for TNF activity. TNF activity both in supernatants and in sera was detected in a 18 h WEHI-164 cell cytotoxicity assay and was confirmed by a monoclonal antibody directed against recombinant human TNF-alpha. Results showed a significant increase in TNF activity from mononuclear cells exposed to MDP or MDP plus LPS of 20% and 88%, respectively; P < 0.0005. Serum TNF activity rapidly increased within 2-3 h post L-MTP-PE injection and subsequently declined to pretreatment level at 4 h post administration. This study demonstrates that MDP +/- LPS can stimulate canine adherent mononuclear cells to release TNF and intravenous injection of L-MTP-PE is capable of rendering the in vivo release of TNF in normal dogs.
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PMID:In vitro and in vivo canine mononuclear cell production of tumor necrosis factor induced by muramyl peptides and lipopolysaccharide. 825 37

Tumor necrosis factor-alpha (TNF-alpha) and blood neutrophils (polymorphonuclear leukocytes; PMNs) have been implicated in the pathogenesis of endotoxin (lipopolysaccharide, LPS) hepatotoxicity. However, the mechanism by which these factors mediate liver injury during LPS exposure is uncertain. The objective of this study was to test the hypothesis that TNF-alpha contributes to LPS hepatotoxicity by an indirect, PMN-dependent mechanism. Pretreatment of rats with an antiserum to TNF-alpha afforded protection against liver injury 6 h after LPS exposure. Pretreatment with pentoxifylline (100 mg/kg i.v.), which attenuated the increase in circulating TNF-alpha concentration 1.5 h after administration of LPS, also afforded protection against liver injury. Neither antiserum to TNF-alpha nor pentoxifylline affected hepatic PMN accumulation 1.5 h after LPS exposure. Depletion of circulating PMNs, which protects against LPS hepatotoxicity, enhanced circulating TNF-alpha concentration compared with control rats 1.5 h after LPS exposure. These results suggest that TNF-alpha contributes to liver injury after LPS exposure, but in the absence of circulating PMNs it is insufficient for full manifestation of liver injury. TNF-alpha apparently contributes to the pathogenesis of LPS-induced liver injury by an indirect, PMN-dependent mechanism.
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PMID:Relationship between tumor necrosis factor-alpha and neutrophils in endotoxin-induced liver injury. 827 51

Peripheral vasodilation is a common feature of warm heart surgery and creates clinical concerns when pressor agents become necessary because of the potential for some of these drugs to adversely affect flow through newly engrafted arterial and venous bypass conduits. The possible role of a temperature-dependent production of cytokines in the pathogenesis of this vasodilation was investigated in a two-part study. In part I, lipopolysaccharide-activated peritoneal rabbit macrophages (5 x 10(6)/ml) were incubated at 30 degrees or 37 degrees C up to 9 hours and the concentration of tumor necrosis factor released in the supernatant was serially measured by a bioassay. Tumor necrosis factor production was found to increase over time for each of the two temperatures of incubation but was significantly higher throughout the observation period in normothermic experiments than in those done at 30 degrees C. Part II was a prospective clinical study involving 30 patients who underwent either cold (core temperature 28 degrees to 30 degrees C, n = 15) or warm (37 degrees C, n = 15) cardiopulmonary bypass and in whom serum levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 were measured by enzyme-linked immunosorbent assays at 2, 4, 10, and 24 hours after bypass. Cytokine levels were found to be consistently higher in patients having normothermic bypass. Differences between the two groups were significant 2 hours after bypass for tumor necrosis factor alpha and interleukin-6 (p < 0.02 and p = 0.0001, respectively) and 4 and 10 hours after bypass for interleukin-1 beta (p < 0.01 and p < 0.04, respectively). The incidence of vasodilation necessitating vasopressor support was twofold higher in the normothermic group (six patients versus three in the hypothermic group). Taken as a whole, patients supported by pressor agents had significantly higher cytokine levels after bypass than those who did not require pressor therapy. Our results suggest that vasodilation occurring with warm heart operation is, at least partly, mediated by a temperature-dependent release of cytokines. Vasodilation might therefore be mitigated by simply allowing the core temperature to drift during bypass. Our recent clinical experience suggests that this "tepid" heart surgery (32 degrees to 34 degrees C) effectively blunts most of the vasodilatory response to strictly normothermic bypass without compromising maintenance of myocardial aerobiosis during arrest.
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PMID:A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines. 828


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