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, a mononuclear phagocyte-derived peptide produced in response to lipopolysaccharide, has been shown to mediate certain aspects of septic shock and multiple organ failure resulting from gram-negative septicemia. In the present investigation, pretreatment of animals with pentoxifylline inhibited lipopolysaccharide-induced serum tumor necrosis factor in a dose-dependent fashion. Pentoxifylline prevented the sequestration of neutrophils seen in animals given intravenous lipopolysaccharide. Furthermore, pentoxifylline protected animals from the lethal effects of an intravenous challenge with lipopolysaccharide. These data indicate that pentoxifylline inhibits lipopolysaccharide-induced tumor necrosis factor and may be an effective agent in mitigating the lethal consequences of sepsis and other disease processes mediated by this cytokine.
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PMID:Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and mortality. 223 23

The purpose of the study was to evaluate the toxicity and biological activity of highly purified lipopolysaccharide (LPS) administered intravenously to cancer patients in order to establish an optimum dosage scheme. An initial subtoxic dose was increased in weekly increments in accordance with individual regimens that maintained patient reaction at a safe and acceptable level. Purified LPS from Salmonella abortus equi was administered to 11 patients with advanced solid tumors on a weekly schedule with intraindividually escalating dosage as determined by patient response. Biological response was monitored by complete blood count, C-reactive protein, and cytokine measurements at different time points after LPS injection. Tumor necrosis factor-alpha (TNF) and interleukin-1 beta serum levels were measured by enzyme-linked immunosorbent assay and interleukin-6 (IL-6) by bioassay. Dose-limiting toxicities including chills and fever (WHO grade III) were reached at 1.0 ng/kg of body weight (maximal tolerated dose-1, MTD-1). Pretreatment with ibuprofen (1,600 mg) abrogated these side effects, allowing further escalation of LPS doses up to 10 ng/kg of body weight. At dose levels greater than 8.0 ng/kg of body weight (MTD-2), the aforementioned side effects occurred again and, additionally, hepatic toxicity (WHO grade III) was observed. Hematological changes included neutropenia followed by a pronounced neutrophilia contributed to by up to 30% bands, marked monocytopenia for 3 h, and retarded lymphopenia. By 24 h, all hematological parameters returned to pretreatment values. TNF serum levels increased from 10 pg/ml before treatment to 7,000 pg/ml as a function of dosage. Maximum serum levels were reached at 60 to 90 min after LPS injection. Similarly, IL-6 serum concentrations increased from less than 4 to 2,500 U/ml; peak levels were obtained 30 min after TNF peak values. Prior administration of ibuprofen had no effect on the above-mentioned hematological changes nor on cytokine release. LPS can be administered intravenously in weekly intervals at escalating doses from 0.15-10.0 ng/kg of body weight, when patients are protected by pretreatment with ibuprofen at dose levels above 1.0 ng/kg of body weight. Cytokine release as measured by TNF and IL-6 increased in a dose-dependent manner although the constitutional symptoms are completely attenuated.
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PMID:Biological response to intravenously administered endotoxin in patients with advanced cancer. 225 60

Tumor necrosis factor-alpha (TNF) has been implicated strongly as a principal mediator in the pathogenesis of septic shock. The authors investigated the in vivo production of TNF in CBA/J and CD-1 mice that had been primed by an intraperitoneal injection of complete Freund's adjuvant followed 2 weeks later by an intraperitoneal injection of lipopolysaccharide (LPS). TNF bioactivity peaked in both the ascites and plasma one hour after challenge, and TNF mRNA expression in the ascites cells peaked 30 minutes after LPS. After the induction of bioactivity, an interstitial pulmonary neutrophilic infiltrate occurred that was quantitated both morphometrically and by a myeloperoxidase (MPO) assay. Peripheral blood neutrophilia and lymphopenia developed after the LPS injection (PMNs: control, 46 +/- 2%; LPS, 65 +/- 3%; Lymphs control, 53 +/- 2%; LPS, 37 +/- 3%). Treatment with dexamethasone (Dex) completely inhibited the pulmonary neutrophilic infiltrate as measured by the (MPO) assay. Because Dex will inhibit the production of several cytokines, anti-TNF antiserum was given to mice at the same time as the LPS challenge to assess specifically the role of TNF in inducing these changes. This antiserum partially blocked the pulmonary neutrophil infiltrate, and completely blocked the peripheral blood changes at one hour after LPS. These data demonstrate that TNF plays an important role in the early pathophysiologic alterations that occur after systemic exposure to LPS.
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PMID:Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations. 229 50

Human hepatoma (HepG2) cells respond to unfractionated conditioned media of human squamous carcinoma (COLO-16) cells and lipopolysaccharide-stimulated human peripheral blood monocytes by increasing the synthesis of alpha 1-acid glycoprotein, haptoglobin, complement C3, alpha 1-antichymotrypsin, alpha 1-antitrypsin, and fibrinogen, while decreasing the synthesis of albumin. The regulation of the acute phase proteins is mediated by hepatocyte-stimulating factors (HSF) and interleukin 1 (IL-1) present in the conditioned medium. Purified HSF-I from COLO-16 cells stimulates preferentially alpha 1-acid glycoprotein synthesis, whereas COLO-HSF-II stimulates preferentially the synthesis of haptoglobin, fibrinogen, and alpha 1-antitrypsin. HSF from monocytes, which has been identified as interferon-beta 2 (B cell stimulating factor-2), displayed the same activity as COLO-HSF-II. Dexamethasone alone had no effect on acute phase plasma protein synthesis but enhanced the response to various HSF severalfold. IL-1 had a relatively low stimulatory activity on the synthesis of alpha 1-acid glycoprotein, haptoglobin, and alpha 1-antichymotrypsin but strongly reduced the basal expression of fibrinogen. The only synergistic action between IL-1 and HSF (or interferon-beta 2) was noted for the synthesis of alpha 1-acid glycoprotein. Tumor necrosis factor active on other hepatic cells failed to modulate significantly the expression of any plasma proteins in HepG2 cells. These studies showed that for an optimal HepG2-cell response a combination of HSF (or interferon-beta 2), IL-1, and dexamethasone is needed. This finding might indicate the identity of some of those hormones involved in regulation of the hepatic acute phase response in vivo.
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PMID:Interaction among hepatocyte-stimulating factors, interleukin 1, and glucocorticoids for regulation of acute phase plasma proteins in human hepatoma (HepG2) cells. 244 59

Tumor necrosis factor-alpha (TNF), a mononuclear phagocyte (MO)-derived peptide, is increasingly being recognized for its pleomorphic immunologic effects. A number of investigations have demonstrated that lipopolysaccharide (LPS) can induce TNF synthesis, yet mechanisms that regulate TNF expression at the cellular and molecular levels have not been fully elucidated. In this study, we present data demonstrating pentoxifylline, a methylxanthine, is efficacious in suppressing LPS-induced MO-derived TNF at the level of both TNF mRNA accumulation and TNF supernatant bioactivity. Pentoxifylline, at a dose of 1 x 10(-5)M, suppressed the production of both biologically active TNF and TNF mRNA expression by more than 50%. Furthermore, additional methylxanthines and dibutyryl cAMP have similar effects on TNF expression. These data support the mechanism for this suppressive effect is via the generation of intracellular cAMP.
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PMID:Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. 246 96

Tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma) have been shown to regulate cell-mediated immunity and act as effective modifiers of immune function; however, their influence on neutrophil (PMN) function is not well defined. This study investigated the effect of these cytokines on PMN phagocytosis, respiratory burst, and complement receptor (C3b) expression. Human citrated whole blood was incubated with either phosphate-buffered saline (control), 20 micrograms Escherichia coli lipopolysaccharide (LPS), TNF (1, 10, or 100 units), or IFN-gamma (1, 10, or 100 units). Synergy was also assessed between TNF and IFN-gamma. Phagocytosis and respiratory burst were assayed by sequential incubation of blood with dichlorofluorescein diacetate followed by labeled Staphylococcus aureus. C3b receptor expression was assayed by labeled anti-CR3 monoclonal antibody. Measurements were expressed as the mean channel fluorescence of 2000 PMNs counted by flow cytometry. IFN-gamma alone at all doses had no effect on any of the parameters measured. TNF 1 unit/ml increased phagocytosis (666 +/- 47 vs 542 +/- 19), respiratory burst (326 +/- 33 vs 258 +/- 17), and C3b (374 +/- 42 vs 157 +/- 14; all P less than 0.05) over those of control. TNF also demonstrated dose-dependent PMN activation. The combination of TNF + IFN-gamma increased both respiratory burst and C3b compared to either agent alone. These data indicate that TNF enhances PMN function and cytokine interaction may be important in PMN activation.
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PMID:The effect of tumor necrosis factor-alpha and interferon-gamma on neutrophil function. 249 85

We have investigated the interaction of interferon-gamma (IFN-gamma) with monocytes or products of stimulated monocytes. We have shown that IFN-gamma does not stimulate IFN-alpha production in monocytes. Staphylococcus aureus (SAC) but not lipopolysaccharide (LPS) induced IFN-alpha secretion by monocytes. However, it was observed that supernatants of monocytes stimulated with IFN-gamma in combination with either LPS or SAC had higher levels of antiviral activity than supernatants of monocytes stimulated only with IFN-gamma. Moreover, the degree of enhancement of antiviral activity was dependent on the dose of either LPS or SAC used to stimulate the monocytes. Supernatants of monocytes stimulated with LPS or SAC enhanced the antiviral activity of IFN-gamma but not IFN-alpha. Thus, LPS- or SAC-stimulated monocytes produced a factor(s) that augmented the biological activity of IFN-gamma. To identify the factor within stimulated monocyte supernatants that was responsible for this enhancement, several monokines were added to IFN-gamma. Tumor necrosis factor (TNF) significantly increased the antiviral activity of IFN-gamma, although TNF by itself had no antiviral activity. Interleukin 1 (IL-1) or granulocyte-monocyte colony-stimulating factor (GM-CSF) did not enhance the activity of IFN-gamma. Our data indicate that the interaction between IFN-gamma and monocytes is bidirectional. Not only can IFN-gamma activate monocytes, but products of stimulated monocytes also enhance the biological activities of IFN-gamma.
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PMID:Products of stimulated monocytes enhance the activity of interferon-gamma. 249 95

Tumor necrosis factor (TNF) is a cytokine which is produced by mononuclear phagocytes upon activation by bacterial lipopolysaccharide (LPS) and various other stimuli. In immune-mediated glomerulonephritis, infiltration of glomeruli by monocytes-macrophages is associated with production of TNF. The purpose of the present experiments was to determine whether mesangial cells could also contribute to glomerular TNF synthesis. TNF activity has been determined in the culture medium of rat mesangial cells using a L-929 fibroblast lytic assay. This activity was detectable only when the cells were exposed to LPS (0.1 to 10 micrograms/ml) and for periods longer than one hour. The cytotoxic factor was identified as TNF since: (1) the lytic activity was completely inhibited by an anti-mouse TNF polyclonal antibody and was associated with suppression of lipoprotein lipase activity in adipocytes; (2) its molecular weight (110,000 daltons) corresponded to that observed for murine TNF under non-denaturing conditions; and (3) mRNA encoding TNF was expressed by mesangial cells two hours after addition of LPS. To assess the mechanisms whereby TNF production was regulated, the role of prostaglandin E2 (PGE2) was determined. LPS caused a dose-dependent increase of PGE2 synthesis by mesangial cells. Treatment by indomethacin promoted a suppression of PGE2 production together with an increase of TNF synthesis, indicating that PGE2 acted in a negative feedback manner to regulate the production of TNF. Addition of PGE2 (0.1 to 300 nM) or 8-bromo cyclic AMP (0.1 to 100 microM) induced similar dose-dependent reductions of TNF synthesis. Thus the inhibitory effect of PGE2 probably required in part cyclic AMP accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. 254 93

Tumor necrosis factor-alpha (TNF), a monokine produced by lipopolysaccharide (LPS)-stimulated macrophages, is an activator of phagocytic functions and may modulate host responses during infection. To determine the effects of LPS on TNF activity and the pulmonary inflammatory response in vivo, we challenged rats systemically or intratracheally with LPS. Intravenous LPS significantly increased serum TNF content from nondetectable levels in control specimens to peak levels at 90 min, which declined to baseline by 3 h. In response to intratracheal LPS, levels of TNF both in bronchoalveolar lavage fluid and associated with alveolar macrophages increased significantly from near nondetectable levels in control animals. Increases in TNF levels were confined to the LPS-challenged compartment. Intravenous LPS resulted in a decrease in the number of peripheral blood neutrophils and in sequestration of these cells within the pulmonary vasculature. In contrast, intratracheal LPS elicited a marked intraalveolar inflammatory response.
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PMID:Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response. 264 68

Ethanol intoxication has been shown to suppress selected functions of the immune system thereby compromising host defense against bacterial infections. Tumor necrosis factor, a secretory protein produced by the macrophage in response to lipopolysaccharide, mediates the inflammatory cascade and stimulates phagocyte functions. Acute ethanol intoxication markedly suppressed both serum and lung tumor necrosis factor elicited in response to lipopolysaccharide. Furthermore, ethanol inhibited intratracheal lipopolysaccharide-induced neutrophil recruitment into the alveoli and prevented the fall in circulating neutrophils in response to intravenous lipopolysaccharide. Thus, the anti-inflammatory effects of ethanol may be secondary to suppression of macrophage-derived tumor necrosis factor.
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PMID:Alcohol suppresses lipopolysaccharide-induced tumor necrosis factor activity in serum and lung. 264 95


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