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)

Using a model of sepsis induced by parenteral challenge of mice with bacterial lipopolysaccharide (LPS), the authors analyzed the in vivo expression of interleukin-1 (IL-1) alpha,beta and tumor necrosis factor (TNF). Both TNF and IL-1 alpha,beta were detected in hepatic sinusoidal macrophages (Kupffer cells), immunohistochemically. Kinetic analysis showed a clear sequence of synthesis. Tumor necrosis factor was produced first, reaching maximal expression at 1 hour after LPS challenge, then rapidly disappeared. IL-1 beta followed, reaching maximal expression at 2 to 3 hours, then dropped off by 6 hours. Interleukin-1 alpha expression reached a peak at 6 hours and had disappeared by 18 hours. Analysis of serum bioactivity also revealed sequential expression that correlated with immunohistochemical findings. Tumor necrosis factor was maximal at 1 hour and IL-1 at 6 hours. The IL-1 bioactivity was not due to interleukin-6 (IL-6), as this was depleted from specimens by immunoabsorption. Also IL-6 bioactivity reached maximal levels at 3 hours, earlier than IL-1. Pretreatment with 4 mg/kg dexamethasone significantly decreased Kupffer cell expression of TNF and IL-1 alpha (about 80% and 60% suppression, respectively) but had less effect on IL-1 beta expression (about 30% suppression). Accordingly, serum levels of TNF were suppressed by 75% while serum IL-1 was decreased by 39%, indicating differential sensitivity of these cytokines to glucocorticoids. Endogenous corticosteroid levels increased as TNF levels decreased, supporting the contention that glucocorticoids regulate TNF synthesis. In contrast, IL-1 levels rose concurrently with corticosterone. These data indicate a sequential activation of cytokine gene expression in vivo, which may be critical to the cascade of events leading to septic shock, and provide evidence that Kupffer cells are a major source of cytokines in endotoxemia. Finally, the differential sensitivity of cytokine expression to glucocorticoids may in part explain the inadequacy of the latter in the treatment of sepsis.
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PMID:In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. 199 64

The production of interleukin-1 (IL-1) by the P388D1 mouse macrophage cell line and by adherent peritoneal exudate cells (PMs) was examined. In vitro IL-1 production by P388D1 cells treated with lipopolysaccharide (LPS) was enhanced by coculture with levamisole (0.1 to 10 microM). Oral administration of levamisole (3 mg/kg) to mice also resulted in potentiation of in vitro IL-1 production by thioglycollate-elicited peritoneal macrophages in response to in vitro LPS stimulation. Potentiation was approximately twofold. IL-1 production in the absence of LPS by either the P388D1 cells or the PMs was nil, and levamisole did not directly stimulate IL-1 production in these cases. IL-1 activity in the culture supernatants was measured by thymocyte comitogenic assays. The immunochemical identify of the thymocyte comitogenic activity as IL-1 alpha was confirmed by neutralization with a specific goat anti-mouse IL-1 alpha antiserum. These results suggest that one mechanism by which levamisole acts to normalize and restore immune responses may be enhancing the signals which enable activated macrophages to secrete IL-1.
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PMID:Enhancement of in vitro lipopolysaccharide-stimulated interleukin-1 production by levamisole. 200 5

Peripheral blood monocytes can be induced by stimuli such as bacterial lipopolysaccharide (LPS) to secrete an array of cytokines. We have studied the effects of interleukin 7 (IL-7) on human peripheral blood mononuclear cells (PBMC) and found that IL-7 is a relatively potent inducer of IL-6 secretion IL-6 protein levels were determined either by the B9 hybridoma growth factor assay or by enzyme-linked immunosorbent assay, and mRNA for IL-6 was analyzed by Northern hybridization. Detailed examination revealed that, among PBMC, monocytes, rather than lymphocytes, were secreting IL-6 in response to IL-7. In contrast to the low concentrations of IL-7 required to stimulate T cell growth and differentiation (as low as 0.1 ng/ml), relatively high concentrations of IL-7 were necessary to induce IL-6 secretion by monocytes (at least 10 ng/ml). An optimal concentration of IL-7 (100 ng/ml) induced monocytes to secrete 10-fold more IL-6 than an optimal concentration of IL-1 beta (10 ng/ml), and almost as much as LPS. However, significantly more IL-7 than IL-1 beta was required to induce detectable levels of IL-6. The kinetics of IL-6 secretion by monocytes were identical in response to IL-7, IL-1 beta, or LPS, with IL-6 protein detectable in culture supernatants as early as 2 h after the initiation of culture. IL-4 was found to markedly inhibit the ability of IL-7 or LPS to induce IL-6 mRNA and IL-6 secretion. In addition to promoting IL-6 production, IL-7 induced the secretion of immunoreactive IL-1 alpha, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) by monocytes. IL-7 also induced monocyte/macrophage tumoricidal activity against a human melanoma cell target, an activity that may be related to the secretion of IL-1 alpha, IL-1 beta, and TNF-alpha. Finally, we used a whole blood culture system as a bridge to in vivo analysis to demonstrate that IL-7 induces cytokine secretion in the absence of culture medium, fetal calf serum, and adherence to plastic. Our data suggest that IL-7, in addition to regulating lymphocyte growth and differentiation, has potent effects on cells of the monocytic lineage. Thus, IL-7 may be an important mediator in inflammation and in the macrophage immune response to tumors.
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PMID:Interleukin 7 induces cytokine secretion and tumoricidal activity by human peripheral blood monocytes. 200 58

High serum levels of endotoxin and cytokines, through which its activity is mediated, have been shown to be associated with disease severity in septic shock and in fulminant hepatic failure. In the present study, we have investigated the ability of activated charcoals (DHP-1 and Adsorba 150C) and uncharged resin (Amberlite XAD-7) to adsorb lipopolysaccharide (LPS) and various cytokines, namely tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma). The capacities of the adsorbents were assessed by measurement of their equilibrium adsorption isotherms for these substances labelled with 125I. There was no single adsorbent that uniformly adsorbed LPS and the cytokines from phosphate buffered saline or human plasma. DHP-1 charcoal was superior to Adsorba 150C for all substances and was the most effective adsorbent for binding LPS, IL-1 alpha and IFN-gamma. Amberlite XAD-7 resin was most effective for TNF, IL-6 and IFN-alpha, but bound little LPS, particularly from human plasma. Ultrafiltration through a membrane which retains substances of molecular weight greater than 50 kD did not filter the cytokines from human plasma, although the molecular weight of the cytokines range from 17 to 22 kD. This demonstrated that, TNF, IL-1, IL-6, IFN-alpha and IFN-gamma readily bind to proteins and/or other large molecules in plasma.
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PMID:Removal of endotoxin and cytokines by adsorbents and the effect of plasma protein binding. 203 48

We have reported previously that anterior pituitary cells released interleukin-6 (IL-6) and that this release was stimulated by lipopolysaccharide (LPS), phorbol myristate acetate (PMA), or agents that increased intracellular cAMP concentrations. We now report that IL-1 stimulates IL-6 release from anterior pituitary cells in vitro. IL-1 alpha and IL-1 beta (0.04-25 ng/ml) significantly increased IL-6 release 3- to 4-fold in a concentration-related manner during 6-h incubations; however, there was no change in extracellular or intracellular cAMP concentrations. IL-1 alpha and IL-1 beta (10 ng/ml), vasoactive intestinal peptide (VIP, 500 nM), prostaglandin E2 (PGE2, 1 microM), and LPS (1 ng/ml) stimulated IL-6 release to a similar degree. In the presence of VIP and PGE2, IL-1 alpha and IL-1 beta increased IL-6 release without any apparent further change in extracellular or intracellular cAMP. Conversely, LPS did not increase cAMP concentrations, and IL-1 did not significantly increase IL-6 release in the presence of LPS. The preexposure of anterior pituitary cells to 1 microM PMA caused the apparent down-regulation of protein kinase C activity because 100 nM PMA was no longer effective to stimulate IL-6 release; however, the ability of IL-1 alpha, IL-1 beta, PGE2, or LPS to stimulate IL-6 release was not altered. In addition, IL-1 alpha and IL-1 beta stimulated IL-6 release in the presence of maximally stimulative concentrations of PMA. The synthetic glucocorticoid dexamethasone (10 nM) significantly inhibited IL-6 release induced by IL-1 alpha, IL-1 beta, or LPS. The separation of anterior pituitary cells on unit gravity BSA gradients generated fractions of IL-6-producing cells that were inducible by LPS and IL-1 beta and separate from the PRL-, ACTH-, GH-, or LH-producing cell fractions. These data suggest that IL-1 stimulates IL-6 release from a subpopulation of anterior pituitary cells via a glucocorticoid-sensitive and non-cAMP-mediated pathway that is different from those pathways used by VIP, PGE2, and PMA.
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PMID:Interleukin-1 stimulates interleukin-6 release from rat anterior pituitary cells in vitro. 203 55

The production and mRNA expression of IL-1 alpha and IL-1 beta by human monocytes was examined after two different stimuli, a protein kinase C (PKC) activator phorbol myristate acetate (PMA) and bacterial lipopolysaccharide (LPS). LPS induced production of high levels of both IL-1 alpha and IL-1 beta protein (quantitated with type-specific ELISA assays), while after PMA stimulation only IL-1 beta protein could be detected. The IL-1 alpha and IL-1 beta mRNA levels quantitated by Northern blotting were in line with the respective protein levels and nuclear run off analysis revealed that PMA did not activate the IL-1 alpha transcription. The production of the IL-1 alpha and IL-1 beta protein as well as the mRNA expression could be inhibited with protein kinase inhibitor H7, but not with HA1004, indicating that PKC activation is essential for the activation of these genes. Thus these data indicate that PKC activation alone is sufficient for the induction of the IL-1 beta gene, but some additional signals (provided by LPS) are required for the activation of the IL-1 alpha gene.
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PMID:Different activation signals are required for the expression of interleukin-1 alpha and beta genes in human monocytes. 204 62

Tumor necrosis factor (TNF), a protein synthesized in response to the endotoxin bacterial lipopolysaccharide (LPS), is the classical mediator of acute hemorrhagic necrosis of tumors. We have demonstrated that interleukin-1 alpha (IL-1 alpha), with a spectrum of activities very similar to those of TNF, also causes acute hemorrhagic necrosis of tumors. Both TNF and IL-1 induce a cascade of events including the synthesis or release of each other. The present studies were thus undertaken to determine whether the hemorrhagic necrosis induced in tumors by IL-1 alpha is due to TNF. Kinetic parameters of IL-1 alpha-induced hemorrhage were similar to those observed with recombinant murine TNF-alpha (TNF-alpha) or LPS in RIF-1 fibrosarcomas in C3H/HeN (endotoxin-sensitive) mice. However, the amount of TNF found in the sera or tumors of animals treated with LPS was more than 20-fold higher than in mice treated with IL-1 alpha, and LPS induced similar degrees of hemorrhagic necrosis, which was measured by determining the packed volume of red blood cells by 59Fe labeling. A low but significantly hemorrhagic dose of IL-1 alpha induced no detectable TNF in tumors. Pretreatment with 250 micrograms of neutralizing antibody to TNF had no effect on IL-1 alpha-induced hemorrhage, whereas TNF-alpha- and LPS-induced hemorrhagic effects were significantly reduced. These results demonstrate an important antitumor activity of IL-1 alpha that appears to be independent of TNF.
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PMID:Acute hemorrhagic necrosis of tumors induced by interleukin-1 alpha: effects independent of tumor necrosis factor. 206 44

Twenty-four patients with rheumatoid arthritis (RA) and 20 normal controls were examined for the ability of their peripheral blood B cells to produce interleukin 1 (IL-1) with or without lipopolysaccharide (LPS). B cells were purified from peripheral blood by negative selection methods (i.e., removal of adherent cells and sheep red blood cell rosette-forming cells, followed by treatment with monoclonal antibodies (OKT3 and OKM1) and complement). The amount of IL-1 in B cell culture supernatants (SN) was measured by thymocyte and fibroblast proliferation assays and an enzyme-linked immunosorbent assay for IL-1 alpha and beta. As a group, cultured B cells from patients with RA, both spontaneously and when stimulated with LPS, produced higher levels of IL-1 than those from normal controls. IL-1 production by RA B cells with LPS had a weak but positive correlation with disease activity. Moreover, RA B cell culture SN with elevated levels of IL-1 had a synergistic effect on the growth of anti-human IgM (anti-mu) stimulated B cells. In separate experiments, the growth of RA B cells was significantly promoted by IL-1 beta both with and without anti-mu stimulation. These results suggest that B cell-derived IL-1 may be involved in the B cell clonal expansion of RA through its own activity as a B cell stimulatory factor.
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PMID:Increased ability of peripheral blood B cells from patients with rheumatoid arthritis to produce interleukin 1 in vitro. 207 29

Actinobacillus actinomycetemcomitans is associated with periodontal disease in children and adults. We report that low concentrations of lipopolysaccharide (LPS) from A. actinomycetemcomitans stimulated human macrophages to increase dramatically their accumulation of mRNA coding for interleukin-1 alpha (IL-1 alpha), IL-1 beta as well as tumor necrosis factor (TNF). Protein levels of IL-1 and TNF alpha also increased. Levels of these mRNAs increased by 4-5 fold as compared with unstimulated macrophages when these cells were cultured with as little as 2 ng/ml LPS from A. actinomycetemcomitans. Polymyxin binds and blocks the action of LPS; polymyxin inhibited the ability of LPS from A. actinomycetemcomitans to increase levels of IL-1 beta mRNA. The LPS of A. actinomycetemcomitans stimulated increased levels of IL-1 beta mRNA in the presence of cycloheximide, showing that stimulation by this LPS did not require new synthesis of protein. Furthermore, dexamethasone inhibited the ability of LPS from A. actinomycetemcomitans to stimulate the accumulation of mRNA coding for IL-1 beta. A. actinomycetemcomitans is an invasive microorganism of the gingiva; high intragingival numbers correlate with sites undergoing local destruction of the periodontium. IL-1 alpha, IL-1 beta, and TNF are potent monokines that mediate inflammation and resorption of bone. Out studies suggest that macrophages migrating to these gingival sites of A. actinomycetemcomitans infection will be stimulated by LPS of A. actinomycetemcomitans to produce IL-1 alpha, IL-1 beta and TNF. These cytokines will mediate gingival inflammation and stimulate resorption of alveolar bone.
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PMID:Lipopolysaccharide from Actinobacillus actinomycetemcomitans stimulates macrophages to produce interleukin-1 and tumor necrosis factor mRNA and protein. 209 99

Gamma interferon (IFN-gamma) can be cytolytic for normal mouse fibroblasts isolated from embryonic or adult tissue (R. Dijkmas, B. Decock, H. Heremans, J. Van Damme, and A. Billiau, Lymphokine Res. 8:25-34, 1989). This cytotoxicity has been shown to be transcription and translation dependent, thereby suggesting involvement of a suicidelike mechanism. The dose of IFN-gamma required for cytotoxicity is higher than that needed for antiviral and macrophage activation but can be reduced 10- to 100-fold by cotreatment of the cells with tumor necrosis factor or interleukin-1 (IL-1) or both, two cytokines that by themselves are not toxic for these cells. Here, we show that bacterial lipopolysaccharide (LPS), which alone has no effect on the viability of mouse fibroblasts, stimulates cell suicide induced by IFN-gamma. The effect was observed in cultures that were virtually free of nonfibroblastoid cells. LPS showed its toxicity-enhancing effect only if applied on the cells simultaneously with or immediately after treatment with IFN-gamma. Pretreatment of the cells with LPS was ineffective. Inclusion of antibodies directed against tumor necrosis factor alpha or IL-1 alpha in the culture medium did not block the cytotoxic effect of combined IFN-gamma plus LPS treatment. The time courses of cell toxicity appearance in fibroblasts treated with combined IFN-gamma plus LPS or IFN-gamma plus IL-1 were similar. In addition to LPS, heat-killed gram-negative (Escherichia coli) but also gram-positive (Staphylococcus aureus, Listeria monocytogenes) bacteria were found to enhance IFN-gamma-induced cell death. These findings suggest that IFN-gamma formed in vivo during infectious processes directly aggravates tissue destruction.
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PMID:Bacterial lipopolysaccharide potentiates gamma interferon-induced cytotoxicity for normal mouse and rat fibroblasts. 210 1


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