Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

Recombinant human interleukin 1 receptor antagonist (IL-1ra) and 35F5, a neutralizing monoclonal antibody (mAb) to the type I mouse IL-1 receptor, were examined for their ability to bind to IL-1 receptors (IL-1Rs) on various types of mouse cells and to block immune and inflammatory responses to IL-1 in vitro and in mice. IL-1ra competed for binding of 125I-IL-1 alpha to type I IL-1R present on EL-4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1 alpha. In contrast, IL-1ra bound with very low affinity (IC50 values ranging from 10 to 200 micrograms/ml) to cells expressing type II IL-1R, i.e., 70Z/3 pre-B cell line and polymorphonuclear leukocytes (PMN) derived from bone marrow and acute inflammatory exudates. The mAb 35F5 bound specifically to type I IL-1R; no inhibition of 125I-IL-1 alpha binding to cells having type II IL-1R was observed with very high concentrations of antibody. While neither IL-1ra nor 35F5 had intrinsic activity in bioassays using T helper D10.G4.1 cells and mouse thymocytes, both agents blocked the ability of IL-1 to stimulate proliferation of these cells. The effects of IL-1ra and 35F5 on acute inflammatory responses in mice were also evaluated. IL-1ra and 35F5 blocked the local accumulation of PMN after intraperitoneal injection of rIL-1 alpha. The response to IL-1 was inhibited when IL-1ra or 35F5 was administered simultaneously with or before administration of IL-1. IL-1ra and 35F5 also blocked PMN accumulation after intraperitoneal injection of lipopolysaccharide or proteose peptone, suggesting IL-1 is important in mediating responses to these agents. In addition, IL-1ra and 35F5 significantly blocked the ability of IL-1 to stimulate egress of PMN from bone marrow, to induce a transient neutrophilia, and to elevate serum levels of hepatic acute phase proteins, IL-6, and corticosterone. Thus, IL-1ra and 35F5 competitively inhibit the binding of IL-1 to the IL-1R on certain cell types. These two IL-1 receptor antagonists act to inhibit biological responses induced by IL-1 and other inflammatory agents.
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PMID:Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. 182 28

Tolerance of monocytes/macrophages to endotoxin (lipopolysaccharide [LPS]) can be induced both in vivo and in vitro by LPS itself. Exposure to LPS, even at a very low dose, induces a downregulation of cytokine response to a second high dose LPS challenge. To learn more about the unknown mechanisms of this phenomenon, we studied the role of antiinflammatory cytokines in this process. Preculture of human peripheral blood monocytes for 24 hours with low concentrations of LPS induced hyporesponsiveness to high-dose LPS rechallenge with respect to tumor necrosis factor (TNF) alpha and interleukin (IL) 10 but not IL-1RA production. These results suggest that LPS tolerance reflects a functional switch of monocytes rather than a general LPS hyporesponsiveness. IL-10 and transforming growth factor (TGF) beta 1 showed additive effects in replacing LPS for induction of LPS hyporesponsiveness in vitro. Additionally, neutralizing anti-IL-10 and anti-TGF-beta monoclonal antibodies prevented induction of LPS tolerance. In vitro induced LPS tolerance looks like the ex vivo LPS hyporesponsiveness of monocytes from septic patients with fatal outcome: downregulation of LPS-induced TNF-alpha and IL-10 production but not of IL-1RA secretion. LPS hyporesponsiveness in septic patients was preceded by expression of IL-10 at both the mRNA and protein level. In summary, our data suggests that IL-10 and TGF-beta mediate the phenomenon of LPS tolerance in vitro and perhaps in vivo (septic patients), too.
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PMID:Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta. 772 63

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 interleukin 1 receptor antagonist (IL-1ra) protein is an inhibitor of the pro-inflammatory cytokine interleukin 1. We have sequenced the mouse gene encoding the monocyte form of IL-1ra (IL-1rn) and compared it with the sequence of the human homologue. In addition to high levels of similarity between the coding regions of the two genes, portions of the introns show surprisingly high levels of identity. In order to develop an in vitro model system to investigate the regulation of IL-1ra induction, three differently responding mouse macrophage cell lines were stimulated with lipopolysaccharide. The kinetics and magnitude of IL-1ra mRNA accumulation was cell-line specific indicating that IL-1ra synthesis in response to inducing agents varies according to the phenotype of the cell. Analysis of the relative transcription rate and the half life of the mouse IL-1ra mRNA indicate that IL-1ra mRNA accumulation in macrophages following LPS treatment is due primarily to an increase in transcription rate rather than to increased stability.
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PMID:The mouse interleukin 1 receptor antagonist protein: gene structure and regulation in vitro. 800 26

This study examined the ability of the recombinant human interleukin 1 receptor antagonist (IL-1ra) to block interleukin 1 (IL-1)-mediated experimental metastases from the A375M human melanoma. In vivo, IL-1ra administrated at concentrations > or = 200 times IL-1 significantly inhibited the increase in lung colonies induced by IL-1 in nude mice. The response to IL-1 was significantly inhibited when IL-1ra was administered simultaneously with or 1 to 3 h before IL-1. In vitro, the incubation of IL-1-activated endothelial cells with IL-1ra prevented the increase in adhesion of A375M melanoma cells. At the same experimental conditions, IL-1ra inhibited the augmented expression of the intracellular and vascular cell adhesion molecules 1 and E-selectin induced by IL-1 on endothelial cells. Lipopolysaccharide, an IL-1 inducer, increased the number of lung colonies in nude mice. IL-1ra injected with or 1 h after lipopolysaccharide inhibited this augmentation, suggesting a role for host-produced IL-1 in metastasis formation.
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PMID:Interleukin 1 receptor antagonist inhibits the augmentation of metastasis induced by interleukin 1 or lipopolysaccharide in a human melanoma/nude mouse system. 826 95

Our previous work demonstrated that hypoxia decreases transcription of the human prostaglandin H synthase-2 (PGHS-2) gene during exposure to lipopolysaccharide (LPS), resulting in decreased prostaglandin E2 (PGE2) synthesis (J. Biol. Chem. 269:32979-32984, 1994). Because PGE2 is reported to inhibit interleukin 1 (IL-1) and tumor necrosis factor (TNF), it is likely that hypoxia, through changes in PGE2, will alter IL-1 and TNF release from the human alveolar macrophage. In addition, like PGHS-2, the TNF and IL-1 promoters contain oxidant-sensitive elements which might be altered by hypoxia. Therefore, we hypothesized that LPS-induced release of TNF and IL-1 would be altered by hypoxia. To test this, human alveolar macrophages were cultured for 24 h with 0 to 1 microgram/ml LPS in a room-air incubator with 5% CO2 or a hypoxia incubator continuously perfused with 5% CO2/95% N2 (O2 < 0.05%). With room air, LPS increased IL-1 beta mRNA and increased IL-1 beta protein release into the culture medium in a dose-dependent manner. Hypoxia increased the LPS-stimulated release of IL-1 beta 30% above that of room-air controls. However, immunoblots showed that hypoxia caused no change in intracellular IL-1 beta compared with room-air controls. There was also no change in LPS-induced IL-1 beta message with hypoxia. The inhibitor of IL-1, IL-1RA, was apparently decreased by hypoxia, but this decrease was not statistically significant. TNF-alpha mRNA and release of protein also increased during LPS exposure in room air. Hypoxia markedly increased LPS-induced TNF-alpha message and release of TNF-alpha compared with LPS-exposed room-air controls. Consistent with our prior observations, hypoxia decreased LPS-induced PGHS-2 message and protein, and also the PGHS-2 product, PGE2. Because PGE2 is reported to inhibit the expression of IL-1 and TNF genes, we inhibited PGE2 synthesis with indomethacin during culture in room air; the result was an increase in the release of IL-1 and TNF. In additional studies, adding PGE2 inhibited TNF release from the hypoxia cells to values near those of room-air controls. In summary, hypoxia increases the release of the cytokines IL-1 beta and TNF-alpha. This increase may be due to decreased PGE2 synthesis during hypoxia. These results demonstrate that the response of the human alveolar macrophage to hypoxia is complex. Hypoxia increases the LPS-stimulated release of the inflammatory cytokines IL-1 and TNF, whereas synthesis of PGHS-2, which generates the anti-inflammatory prostaglandin PGE2 is decreased.
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PMID:Effect of hypoxia on release of IL-1 and TNF by human alveolar macrophages. 863 Feb 67

The modulation of cytokine release induced by pentoxifylline (PTX) has recently been demonstrated not to be restricted solely to tumor necrosis factor (TNF)-alpha. This prompted us to study the influence of PTX on a larger spectrum of cytokines with proinflammatory actions [TNF-alpha, interleukin-6, (IL)-6, IL-1 beta, IL-8] or with implied actions in the TH1 (IL-2, IFN-gamma)/TH2 (IL-10) balance. The IL-1RA was also explored. This work was performed using a whole-blood model in which cytokine production is measured after stimulation by lipopolysaccharide (LPS) (25 micrograms/ml) and phytohemagglutinin (PHA) (5 micrograms/ml) in 1:10 diluted whole blood. The stimulation test was performed in blood from healthy controls and from septic patients (without septic shock) in the presence or absence of PTX at 10(-6), 10(-5), 10(-4), or 10(-3) M. In controls and septic patients, at a 10(-4) M PTX concentration the production of IL-2 is strongly diminished (26-32% of the basal level), followed by diminution of IFN-gamma (30-40%). As expected, of the proinflammatory cytokines TNF was the most strongly suppressed (50% of baseline) followed by IL-1 (about 80% of basal production). Finally, IL-10 was also influenced by PTX (65% of baseline). At 10(-4) M, IL-1RA and IL-6 were unaffected by PTX. Taken altogether, our data demonstrate that PTX possesses a much broader spectrum of activity on cytokine production than was initially described, and it appears to be a potential and promising immunotherapeutic agent.
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PMID:Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. 869 68

The activities of monocyte-derived tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta are potentially modified by IL-1RA and soluble receptors for TNF (sTNF-R), which are themselves monocyte products. IL-4, IL-10, TGF-beta, and glucocorticoids (GC) all suppress the lipopolysaccharide (LPS)-stimulated release of TNF-alpha and IL-1beta but vary in their effects on IL-1RA and sTNF-R. This raises the prospect of interactions between the cytokines and glucocorticoids, which may be antagonistic or additive on IL-1 and TNF activity. We, therefore, studied the interactions of the GC dexamethasone (Dex) with IL-4, IL-10, and transforming growth factor (TGF)-beta on the release of TNF-alpha and IL-1RA by human monocytes and the monocytic THP-1 cell line. Low concentration of Dex (10(-8)-10(-7)M) acted additively with low concentrations of IL-4 (0.01-1 ng/ml), IL-10 (0.01-0.1 U/ml), or TGF-beta (0.01-1 ng/ml) to profoundly suppress LPS-stimulated release of TNF-alpha by whole blood and, to a lesser degree, THP-1 cells. Dex also suppressed spontaneous release of IL-1RA from PBMC and THP-1 cells, whereas IL-4 and IL-10, but not TGF-beta, stimulated release. Dex antagonized the enhanced release in IL-4 and IL-10-stimulated cultures. The capacity to stimulate release of IL-1RA may contribute to the anti-inflammatory potential of IL-4 and IL-10 in monocyte/macrophage-mediated disease. GC, therefore, do not uniquely enhance the suppressive functions of IL-4 and IL-10 on monokine activity. The therapeutic benefit of combinations of GC and IL-4, IL-10 or TGF-beta in disease may depend on the roles of the individual monokines and antagonists in pathogenesis.
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PMID:Dexamethasone antagonizes IL-4 and IL-10-induced release of IL-1RA by monocytes but augments IL-4-, IL-10-, and TGF-beta-induced suppression of TNF-alpha release. 883 16

Mycoplasma arthritidis is an arthritogenic organism for rodents, producing a superantigen (MAS). It has been postulated that mycoplasmas or superantigens thereof might play a role in human rheumatoid arthritis. Since M. arthritidis fulfills both, the present study was performed to investigate MAS-specific cytokine induction. Human or murine leukocytes were stimulated with MAS, staphylococcal enterotoxin E (SEE), or lipopolysaccharide (LPS). Cytokines were measured by ELISA, Bioassay, and RT-PCR. The response to MAS in humans was individually restricted, in contrast to the response to SEE or LPS. Furthermore, MAS showed the same capacity for inducing proinflammatory cytokines as interleukin (IL)-1 IL-6, and IL-8 as SEE and LPS. However, MAS showed a significantly decreased capacity to induce the anti-inflammatory cytokine IL-10 and IL-1RA. In mice, the reactivity to MAS was strictly MHC-II restricted, in contrast to that of SEE or LPS. The individual response to MAS in humans might be explained by the difference of the HLA-DR haplotype because H-2-differing mouse strains showed the same discrepancies. MAS induced an overproduction of proinflammatory cytokines, when its ability to induce proinflammatory and anti-inflammatory cytokines was compared with those of SEE and LPS. The individual response may explain an MHC linkage, and the failure to induce anti-inflammatory cytokines may be the reason for a chronic disease in contrast to acute inflammation.
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PMID:Induction of a proinflammatory cytokine network by Mycoplasma arthritidis-derived superantigen (MAS). 891 Jul 72


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