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)

This investigation was designed to elucidate whether an intracellular version of interleukin 1 receptor antagonist (icIL-1ra) interferes with the action of IL-1 at the level of vascular cells. Recombinant icIL-1ra inhibited the IL-1-induced production of IL-6, IL-8 and monocyte chemotactic protein by human endothelial cells (HEC). Moreover, icIL-1ra inhibited induction of adhesion molecules by IL-1. Endotoxin lipopolysaccharide (LPS), an IL-1 inducer, stimulated a spectrum of functions in EC similar to that activated by IL-1, but icIL-1ra did not interfere with the LPS activation of EC. This observation suggests that induction of extracellular IL-1 is not an important intermediate event in the response of EC to LPS. Unlike LPS-stimulated monocytes, EC exposed to different inducers did not express appreciable levels of IL-1ra mRNA transcripts as assessed by northern blot analysis. IL-1ra produced by mononuclear phagocytes, represents a negative regulator circuit of the action of IL-1 on EC and could be important in the control of vascular participation in inflammation and immunity.
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PMID:Inhibitory effect of recombinant intracellular interleukin 1 receptor antagonist on endothelial cell activation. 137 16

Interleukin 1 (IL-1) is an endogenously produced cytokine that mediates a variety of physiological effects that may be beneficial or deleterious to the host. C57Bl/6 mice treated intravenously with a recently characterized human recombinant receptor antagonist protein to IL-1 (IL-1ra) had improved survival when treated after a lethal Escherichia coli endotoxin (lipopolysaccharide [LPS]) challenge. IL-1ra was effective when treatment was initiated after LPS, and intravenous administration every 4 h for 24 h was required. Serum levels of tumor necrosis factor (TNF) activity after LPS and in vitro TNF cytotoxicity were not altered by treatment with IL-1ra. These experiments provide direct evidence that the lethal effects of LPS may be mediated through the action of IL-1 and that the IL-1ra can provide a new treatment strategy for disease processes mediated via this cytokine.
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PMID:A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. 182 27

Mononuclear cells (MNC) stimulated either with lipopolysaccharide (LPS) or with surface-adsorbed IgG elaborated significant amounts of tumor necrosis factor (TNF) bioactivity, as well as immunoenzymatically detectable TNF-alpha and interleukin-1 beta. (IL1-beta). In contrast, IgG-stimulated cells released little IL1 bioactivity, but released an IL1 inhibitor, as determined by the thymocyte costimulatory assay (LAF assay). This inhibition was not due to an inhibitory effect of cyclooxygenase products, e.g. prostaglandin-E2 in the LAF assay. In contrast, antibodies against transforming growth factor type beta (TGF-beta), which is an important inhibitor of the LAF assay, augmented the LAF activity of supernatants from LPS-stimulated and IgG-stimulated MNC. Anti-TGF-beta-modulated LAF inhibition was enhanced by acid treatment of supernatants from mononuclear cells, but not of those from purified monocytes. Antibody blocking experiments point for the first time to a TGF-beta species other than type 1 as a monocyte-derived TGF-beta activity. Thus, TGF-beta released in active form from monocytes may be the more important antagonist of IL1 than cyclooxygenase-derived mediators. It implies that the LAF assay, in the absence of anti-TGF-beta antibodies, is an inadequate indicator of IL1 activity.
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PMID:IGG-stimulated and LPS-stimulated monocytes elaborate transforming growth factor type beta (TGF-beta) in active form. 199 79

In this study the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1 beta (IL-1 beta) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described. An in vivo microdialysis method was used to measure hippocampal extracellular concentrations of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in conscious, freely moving rats. In addition, we established a method to continuously monitor free corticosterone levels in dialysates. Behavioral activity was scored by measuring the time during which rats were active (locomotion, grooming, eating, drinking). We found a significant, positive relationship between behavioral activity and hippocampal extracellular concentrations of 5-HT. Intraperitoneal (i.p.) administration of the bacterial endotoxin lipopolysaccharide (LPS; 30, 100, and 300 micrograms/kg body weight) produced an increase in the extracellular concentrations of 5-HT and 5-HIAA in the hippocampus, which was paralleled by a significant decline in behavioral activity and a marked increase in extracellular corticosterone levels. Thus, the close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS-treated animals. The effects of i.p. LPS could be mimicked by i.c.v. application of recombinant human IL-1 beta (hIL-1 beta; 100 ng). i.c.v. pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 micrograms) antagonized the hIL-1 beta-induced effects. IL-1ra showed no intrinsic effects. Furthermore, it was found that i.c.v. pretreatment with IL-1ra (10 micrograms) significantly attenuated the i.p. LPS-induced (100 micrograms/kg body weight) rise in hippocampal extracellular 5-HT levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. 753 23

The marine natural products manoalide and scalaradial are potent anti-inflammatory agents that inactivate the enzyme phospholipase A2 (PLA2) in vitro. To study the mechanism of inhibition of prostaglandin E2 (PGE2) production in human monocytes by manoalide and scalaradial, lipopolysaccharide (LPS)-induced prostaglandin biosynthesis and induction of prostaglandin H synthase (PGHS) were evaluated. LPS (10 ng/mL) and interleukin-1 beta (IL-1 beta, 50-1000 ng/mL) but not tumor necrosis factor alpha (TNF alpha, 300 ng/mL) induced the expression of the PGHS-2 isoform as determined by immunoblot analysis with a specific polyclonal antibody for PGHS-2. Manoalide and scalaradial (1-10 microM) inhibited LPS-induced endogeneous PGE2 production, reduced the LPS-induced PGHS activity, and reduced the expression of PGHS-2. Indomethacin [a PGHS inhibitor (0.01 to 0.1 microM)], zileuton [a 5-lipoxygenase inhibitor (3-10 microM)], and WEB-2806 [a platelet-activating factor (PAF) antagonist (30 microM)] did not affect the LPS-induced expression of PGHS-2 in human monocytes. These results suggest that modulation of lipid mediator production by manoalide or scalaradial may not be involved in the observed effects on the expression of PGHS-2. Manoalide and scalaradial also inhibited the release of IL-1 beta and TNF alpha from LPS-stimulated monocytes. Expression of PGHS-2 induced by either LPS or IL-1 beta was blocked by the IL-1 receptor antagonist (IL-1ra, 2 micrograms/mL) but not by rolipram, a phosphodiesterase IV inhibitor that inhibits TNF alpha but not IL-1 beta release. Similar to LPS, IL-1 beta-induced PGHS-2 expression was apparently not regulated by lipid mediators such as prostaglandins, leukotrienes or PAF as determined with specific inhibitors and antagonists. Scalaradial and to some extent manoalide were capable of blocking the IL-1 beta-induced expression of PHGS-2. These results indicate that IL-1 beta is the predominant cytokine responsible for the induction of PGHS-2 in the human monocyte. Furthermore, marine natural products such as scalaradial have novel effects on the IL-1 beta-mediated induction of PGHS-2 in human monocytes, which appears to be independent of effects on lipid mediator production.
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PMID:Regulation of prostaglandin H synthase 2 expression in human monocytes by the marine natural products manoalide and scalaradial. Novel effects independent of inhibition of lipid mediator production. 757 73

1. The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and carrageenin were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to bradykinin (1 micrograms) were inhibited in a dose-dependent manner by prior treatment with IL-10 (1-100 ng). 3. Hyperalgesic responses to TNF alpha (2.5 pg), IL-1 beta (0.5 pg) and IL-6 (1.0 ng) but not to IL-8 (0.1 ng) and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4. Hyperalgesic responses to carrageenin (100 micrograms) were inhibited by IL-10 (10 ng) when this cytokine was injected before but not after the carrageenin. 5. A monoclonal antibody to mouse IL-10 potentiated the hyperalgesic responses to carrageenin (10 micrograms) and TNF alpha (0.025 pg) but not that to IL-8 (0.01 ng). 6. In in vitro experiments in human peripheral blood mononuclear cells (MNCs), IL-10 (0.25-4.0 ng ml-1) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with IL-1 beta (1-64 ng ml-1) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-1) but evoked only small increases in IL-1ra production. 7. These data suggest that IL-10 limits the inflammatory hyperalgesia evoked by carrageenin and bradykinin by two mechanisms: inhibition of cytokine production and inhibition of IL-1 beta evoked PGE2 production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-Ira and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).
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PMID:Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10. 758 91

Airway inflammation is an important aspect of asthma. Recent studies of airway inflammation in asthma have focused attention on cytokines released by T helper lymphocyte type 1 (Th1)- and Th2-like T cells. Interleukin (IL)-1 is also increased in the airways of asthmatics, and it is most likely derived from airway and alveolar macrophages. The effects of Th1 or Th2 cytokines on the release of IL-1 or its specific antagonist, IL-1ra, have not been well studied. We examined the response of THP-1 cells, a myelomonocytic cell line, to stimulation with various Th1 and Th2 cytokines and found that IL-4, IL-10, and IFN-gamma increased IL-1ra mRNA and protein release. The increase in mRNA was not due to an increase in IL-1ra mRNA stability. IL-4 (10 ng/ml) increased IL-1ra release from 9,641 +/- 322 [from cells stimulated with lipopolysaccharide (LPS) alone] to 50,796 +/- 1,917 pg/ml (from cells stimulated with LPS and IL-4). IL-10 (10 ng/ml) caused a similar upregulation of IL-1ra from LPS-stimulated cells: 87,478 +/- 7,808 compared with 8,004 +/- 1,166 pg/ml released from the cells stimulated with LPS alone. Cells stimulated with IFN-gamma (100 U/ml) and LPS released 27,854 +/- 3,626 pg/ml of IL-1ra, compared with 9,069 +/- 236 pg/ml in the presence of LPS alone. In addition, the Th1 cytokine, IFN-gamma, but not the Th2 cytokines, IL-4 and IL-10, upregulated IL-1 beta mRNA and increased the release of IL-1 beta protein. Similar studies were performed using freshly isolated monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of interleukin-1 receptor antagonist by Th1 and Th2 cytokines. 763 20

We investigated the nature of cytokines synthesized by human osteoarthritic (OA) synovium, particularly interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) to block the synthesis of metalloproteases (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthritis (OA) synovium. Human OA synovium were incubated in the presence or absence of lipopolysaccharide (LPS) or increasing concentrations of rhIL-1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-1ra in culture medium were carried out using specific ELISA. Although both IL-1 isoforms and TNF alpha could be produced by OA synovium, IL-1 beta was the predominant cytokine synthesized either in the presence or absence of LPS. Treatment of the OA synovium with an increasing concentration of rhIL-1ra (0-10 micrograms/ml) showed a dose dependent reduction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated synovium also showed a consistent suppression of metalloproteases and IL-6, although a higher IL-1ra concentration was required. Conversely, IL-1 beta production was not inhibited by IL-1ra, irrespective of the concentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine involved in the stimulation of metalloproteases and IL-6 synthesis in OA synovium.
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PMID:Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. 775 12

The aim of the present thesis was to summarize some important immunological mechanisms in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis (CF). The continuous presence of bacteria in the lungs induce a strong immunological response in the patients both locally in the lungs and systemically with high amounts of circulating specific anti-P. aeruginosa antibodies. Our work has been concentrating on anti-lipopolysaccharide (LPS) antibodies. We have shown an increasing antibody response in CF patients, to all three parts of the LPS molecule; lipid A, core, and O-sugars, during the course of chronic P. aeruginosa infection. The antibodies belonged to both IgA, IgM, and all four subclasses of IgG, and were detected in serum and sputum. We detected immune complexes (IC)s in sputum from chronically infected CF patients. The ICs were composed of P. aeruginosa LPS and immunoglobulins of both IgG1-4, IgA and IgM. The concentration of circulating ICs were significantly higher in chronically infected patients compared to non-infected CF patients. The presence of ICs containing LPS in sputum were positively correlated to the amount of tumor necrosis factor alpha (TNF alpha) in the same sputum sample. TNF alpha is a very potent inflammatory mediator, stimulating cells for release of several cytokines attracting polymorphonuclear neutrophil granulocytes (PMNs), which release proteolytic enzymes and toxic oxygen radicals. We detected high concentrations of both TNF alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, and the IL-1 receptor antagonist (IRAP) in sputum from chronically infected CF patients. The corresponding concentrations of the cytokines in serum were low or undetectable. Relatively high concentrations of serum-IRAP before the diagnosis of chronic P. aeruginosa infection were correlated to development of poor pulmonary function. We made ICs in vitro of purified P. aeruginosa LPS and hyperimmune serum from chronically infected CF patients. The biological activity of these ICs was investigated in two different assays. LPS by itself induced TNF alpha liberation in vitro, but the ICs made in vitro were also able to stimulate TNF alpha release from mononuclear cells, and they were a more potent stimuli compared to the corresponding amount of LPS alone. The IC preparation did also induce an oxidative burst response in PMNs. We conclude P. aeruginosa LPS is biological active and formation of ICs involving P. aeruginosa LPS and anti-LPS antibodies takes place in the lungs of chronically infected CF patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lipopolysaccharide (LPS), LPS-immune complexes and cytokines as inducers of pulmonary inflammation in patients with cystic fibrosis and chronic Pseudomonas aeruginosa lung infection. 775 34

The appearance of endogenously produced inhibitors against tumor necrosis factor (TNF) (soluble TNF-receptor type I, sTNFR-I) and interleukin-1 (IL-1 receptor antagonist, IL-1ra) was evaluated acutely in five normal patients after experimental endotoxemia lipopolysaccharide (LPS) and prospectively during a one to 11 week period in 12 septic, critically ill patients. Increased levels of both factors remained detectable in the circulation for up to 24 hours after LPS (2 nanograms per kilogram body weight) administration in normal patients. Despite free TNF-a activity being detected only sporadically (3 percent of the samples) and that IL-1 beta was never detectable in the patients in the intensive care unit, IL-6 bioactivity was present in 90 percent of initial samples. Circulating sTNFR-I levels up to 62,000 picograms per milliliter and IL-1ra levels of 14,800 picograms per milliliter were noted in the critically ill patients and remained consistently detectable throughout the extended period of evaluation. While there was no difference in IL-1ra levels between patients who survived or ultimately died, sTNFR-I levels were significantly (p < 0.001) lower in survivors compared with nonsurvivors. A correlation between circulating sTNFR-I and concurrent cortisol levels (r = 0.64; p < 0.002) was also noted. Furthermore, a correlation between sTNFR-I and the severity of initial insult, as assessed by APACHE II scores (r = 0.54; p < 0.01) was demonstrable. These naturally occurring cytokine antagonists likely represent additional indicators of the presence of an infectious or other inflammatory process and seem to persist in the circulation even during conditions in which their respective proinflammatory cytokines are not demonstrable.
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PMID:Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients. 817 22


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