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)

Endotoxin [lipopolysaccharide (LPS)] is a potent inflammatory stimulus and can activate human umbilical vein endothelium (HUVE) for leucocyte adhesiveness and transendothelial migration. Here we investigated the role of HUVE-secreted cytokines in this process. When HUVE monolayers were grown on filters and preincubated for 3 hr with LPS, 51Cr-labelled polymorphonuclear leucocytes (PMNL) migrated across the HUVE in a dose- and time-dependent manner. Maximal PMNL transmigration with LPS (1 ng/ml) was 26 +/- 3% of added PMNL in 75 min. Neutralizing antibodies to interleukin-1 alpha (IL-1 alpha) and IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-8 or recombinant IL-1 receptor antagonist had no effect on the activation by LPS of the HUVE for supporting migration of PMNL. The HUVE 'activated state' declined with prolonged (22 hr) exposure to LPS, as reflected by a decrease in PMNL transendothelial migration to 5.5 +/- 1% and in the expression of the endothelial cell adhesion molecule, E-selectin, as compared to stimulation with LPS for 3 hr. However, simultaneous exposure to interferon-gamma (IFN-gamma) (200 IU/ml) and LPS maintained maximal PMNL transendothelial migration (28 +/- 4%) for at least 24 hr, prolonged E-selectin expression by HUVE and superinduced intracellular adhesion molecule-1 (ICAM-1) expression. The PMNL transendothelial migration was blocked by > 90% by monoclonal antibody (mAb) to CD18 with either 3 hr of LPS or 22 hr LPS + IFN-gamma stimulation. Migration was partially inhibited by mAb to E-selectin (30-40%) or to ICAM-1 (35-45%) and by a combination of both reagents (50-60%) under both stimulation conditions. Thus, LPS activation of HUVE for PMNL transendothelial migration: (a) does not require secretion of IL-1, TNF-alpha or IL-8 by the endothelium, (b) IFN-gamma enhances and prolongs endothelial activation by LPS and may increase leucocyte infiltration in LPS or bacterial inflammatory reactions, and (c) CD18-dependent mechanisms are equally important for PMNL transendothelial migration under both acute (3 hr) and prolonged (22 hr LPS + IFN-gamma) activation of endothelium.
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PMID:Endotoxin activation of endothelium for polymorphonuclear leucocyte transendothelial migration and modulation by interferon-gamma. 810 89

The avidity of leukocyte integrin CR3 (Mac-1, CD11b/CD18, alpha m beta 2) on neutrophils (PMN) may be rapidly modulated by several agonists. We describe a method for determining the avidity of these receptors by measuring the adhesion of PMN to fibrinogen-coated surfaces. Cells are loaded with a succinimidyl ester of carboxyfluorescein diacetate, which is deacetylated by intracellular esterases yielding a highly fluorescent carboxyfluorescein that remains trapped within the PMN. The number of cells adhering to fibrinogen-coated wells of Terasaki microplates is quantitated with a fluorescence plate reader. Stimulation of PMN with a number of agonists, including PMA, fNLLP, Ca-ionophore A23187, interleukin-8, tumor necrosis factor and lipopolysaccharide strongly increased adhesion to fibrinogen, which was CD11b/CD18 dependent. The extent of cell adhesion depended on stimulus concentration and incubation time. This assay requires little time, utilizes small numbers of cells and does not require hazardous reagents.
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PMID:A fluorescence microassay for the quantitation of integrin-mediated adhesion of neutrophil. 820 64

An analysis of receptor modulation on the neutrophil cell surface is essential for gaining insight into the activation and function of neutrophils in host defense. Moreover, agents that regulate the expression of surface receptors may have profound implications in the management of host response to infection. With this study, we extend previous observations in isolated cells of the putative ability of methylprednisolone sodium succinate (MPSS) to inhibit ligand binding to the formyl peptide receptor. Because neutrophils are exquisitely sensitive to isolation conditions, we have analyzed the regulation of receptor expression using flow cytometry in whole blood. This technique allows discrimination of neutrophils from other formed elements without isolation. Quiescent cells in blood exhibit low levels of formyl peptide receptor, CD11b/CD18, and CD14. We show that MPSS blocks upregulation of each of these receptors in response to three different stimuli (formyl peptide, lipopolysaccharide, and granulocyte macrophage colony-stimulating factor). The inhibition is reversible with an ED50 of approximately 0.4 mg/ml. From these observations, we conclude that the action of MPSS on neutrophils blocks a common response of receptors. Since these receptors probably function in part through independent signaling pathways, MPSS may function at a common site related to vesicular trafficking. Further investigation is needed to determine the specific means by which corticosteroids interfere with neutrophil upregulation mechanisms.
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PMID:Methylprednisolone inhibits three classes of neutrophil receptors in human blood in vitro. 824 97

Modulation of the cellular antigens and regulation of the phagocytic activity of the monocyte-like cell line U937 after culture with lipopolysaccharide (LPS) were investigated. CD14 expression was induced on the surface of the U937 cells after 48 h of culture with LPS and then they became adhesive with numerous filamentous filopodia extruded on the cell surface, exhibiting the enhanced expression of CD16 and CD23, the activation cell surface markers for differentiation into macrophage. However, no induction or enhancement of the cell surface expression was observed with respect to CD11b, CD18, HLA-A, B, C, HLA-DR, DQ, DP or CD57. These U937 cells also acquired the ability to produce superoxide anions and to phagocytose the Salmonella enteritidis strain, 116-54. This phagocytosis was inhibited by the anti-CD11b monoclonal antibodies, but not by the anti-CD14, anti-CD16, anti-CD18, anti-CD23, anti-HLA-A, B, C or anti-HLA-DR monoclonal antibodies. These findings indicate that the phagocytic activity against Salmonella enteritidis 116-54 induced by LPS is mediated mainly via the CD11b molecule, but is not associated with the increased expression of CD11b. Puromycin and cycloheximide, inhibitors of protein synthesis, or a divalent cation-chelating agent, EDTA completely inhibited this phagocytic activity. Interestingly, EDTA was found to suppress specifically the CD11b expression on the U937 cells cultured with LPS. No phagocytic activity was induced when the U937 cells cultured with LPS were incubated at 4 degrees C, but restored to the control level when shifted up to 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of cell surface antigens and regulation of phagocytic activity mediated by CD11b in the monocyte-like cell line U937 in response to lipopolysaccharide. 828 85

The mechanism of neutrophil (PMN) emigration into the lung may be stimulus-dependent. This study examined PMN emigration in the lung induced by intratracheal instillation of lipopolysaccharide (LPS), Streptococcus pneumoniae (S. pneu) organisms, supernatant from S. pneu incubated with alveolar macrophages (AM phi), Escherichia coli (E. coli) organisms, or phorbol myristate acetate (PMA). Rabbits were pretreated with either the CD18 monoclonal antibody (MAb) 60.3, the protein synthesis inhibitor cycloheximide (Cx), or, in one case, both. Animals were then given one of the above stimuli to elicit PMN emigration. Four hours after the stimulus was instilled, animals were killed and total and differential cell counts were performed on bronchoalveolar lavage (BAL) fluid. PMN emigration in response to PMA was virtually abolished by MAb 60.3, but was not significantly inhibited by Cx. Emigration induced by LPS was inhibited by 80% by either MAb 60.3 or Cx, and greater than 94% when MAb 60.3 and Cx were given simultaneously. Emigration in response to E. coli organisms was 80% inhibited by MAb 60.3. Emigration induced by S. pneu was approximately 50% inhibited by MAb 60.3, but was greater than 90% blocked by Cx. The MAb 60.3 had approximately the same effect on PMN emigration toward the supernatant from co-incubation of AM phi with S. pneu as it did toward live S. pneu. It is concluded that the mechanism of PMN emigration into the lung is stimulus-dependent. The CD18-dependent mechanism is responsible for the majority of the emigration in response to PMA, E. coli LPS, and E. coli organisms. S. pneu and supernatant from S. pneu + AM phi produce a CD18-independent pathway. These data suggest the requirement for de novo protein synthesis for PMN emigration in response to LPS and S. pneu, but not for PMA-induced emigration.
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PMID:Role of protein synthesis and CD11/CD18 adhesion complex in neutrophil emigration into the lung. 846 63

Cytokine-induced neutrophil chemoattractant (CINC) is a member of the chemokine alpha sub-family. It is induced in rats by tumor necrosis factor-alpha (TNF-alpha), interleukin-1, and lipopolysaccharide and is implicated in neutrophil infiltration in response to inflammatory stimuli. We tested the hypothesis that pretreatment with anti-CINC antibody or by cobra venom factor attenuates hepatic neutrophil accumulation induced by a 90 min infusion of Escherichia coli endotoxin. Changes in the expression of CD11b/c and CD18 and in plasma TNF-alpha levels were also investigated. Cultured hepatocytes and Kupffer cells of endotoxic rats produced significantly more CINC than those of saline-infused controls. CINC generation by Kupffer cells was much lower than generation by hepatocytes. Pretreatment with anti-CINC antibody or cobra venom factor significantly reduced hepatic neutrophil sequestration, but did not affect the up-regulation of CD11b/c and CD18 expression on liver-sequestered neutrophils or plasma TNF-alpha levels. We conclude that CINC-mediated hepatic neutrophil accumulation may not be necessarily associated with up-regulation of neutrophil adhesion molecules or elevated circulating TNF-alpha levels. Attenuation of hepatic neutrophil sequestration by anti-CINC antibody is likely based on blocking of the chemotactic activity of CINC and thus diminishing the chemotactic gradient established in the liver.
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PMID:Attenuation of hepatic neutrophil sequestration by anti-CINC antibody in endotoxic rats. 856 54

Inflammation is characterized by the migration of polymorphonuclear leukocytes from the vasculature into the tissue causing profound injury. Adhesion and migration of neutrophils across the vascular bed are governed by a series of complex events including cytokine/chemokine production which in turn orchestrates the temporal expression of a cohort of adhesion molecules mediating the migration. Many of these adhesion molecules and their inducers are under the control of inflammatory response transcriptional factors such as NF kappa B and AP-1. Recently we showed tepoxalin, previously known as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, to be a potent inhibitor of NF kappa B-induced transcription in vitro. In this study, we demonstrated that when administered in vivo, tepoxalin but not naproxen (a nonsteroidal anti-inflammatory drug, NSAID) or zileuton (an LO inhibitor), effectively inhibits neutrophil migration into inflammatory sites in murine skin stimulated by either lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Immunohistochemical analysis indicates that 10-50 mg/kg of tepoxalin inhibits neutrophil migration. It also effectively blocks the upregulation of Mac-1 (CD11b/CD18) on neutrophils. Quantitative polymerase chain reaction Mac-1 analysis shows that LPS-induced transcription of E-selectin mRNA was dramatically suppressed by both 25 and 50 mg/kg of tepoxalin, whereas the level of ICAM-1 was only affected by 50 mg/kg of tepoxalin. Since it has been documented that the expression of E-selectin and Mac-1 is regulated either directly or indirectly by the transcription factor NF kappa B, our studies provide in vivo evidence that tepoxalin is a potent inhibitor of NF kappa B-mediated events in animal models and this novel molecular mechanism clearly defines it as a new class of anti-inflammatory compounds.
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PMID:Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression. 856 54

Human polymorphonuclear leucocytes (PMN) express proteins that protect them from damage by homologous complement. Protection may be particularly important when these cells migrate to inflammatory sites where complement activation is taking place. Resolution of inflammation involves removal of these PMN. The major mechanism of removal is likely to involve PMN apoptosis followed by recognition and engulfment by macrophages. However, little attention has been paid to the possible relevance of apoptosis to PMN susceptibility to immune effectors. Here we describe a reduction in cell surface expression of two complement regulatory proteins, CD59, an inhibitor of the membrane attack complex and CD55 (decay accelerating factor), an inhibitor of the C3/C5 convertase, on a subpopulation of PMN aged in culture. Loss of these proteins, both attached to the membrane by glycosyl phosphatidylinositol (GPI) anchors, correlated closely with the appearance of apoptotic morphology. We also observed a marked reduction in expression of the GPI-anchored molecule CD16 on apoptotic PMN. Reduced expression of membrane proteins was not confined to those anchored through GPI--several transmembrane molecules including CD11a CD11b and CD18 were also reduced on apoptotic PMN, whilst other were little changed (CD35, CD46). The precipitous fall in CD16 surface expression on PMN was not specific for apoptosis--in vitro incubation of PMN with lipopolysaccharide-inhibited apoptosis but caused a reduction in CD16 expression to 'apoptotic' levels.
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PMID:Apoptosis is associated with reduced expression of complement regulatory molecules, adhesion molecules and other receptors on polymorphonuclear leucocytes: functional relevance and role in inflammation. 856 34

We have investigated the requirement of neutrophil emigration and the role for CD11b/CD18-mediated events in the experimental induction of acute lung injury. BALB/c mice received lipopolysaccharide (LPS) (3 mg/kg) intravenously (i.v.) 2 h prior to i.v. zymosan (10 mg/kg) and extravascular albumin accumulation was assessed after 30 min. Compared with saline-treated controls, zymosan alone caused a 6-fold increase in the accumulation of 125I-human serum albumin in whole lung tissue (P<0.05). Combined treatment with LPS and zymosan further increased extravascular albumin accumulation (P<0.05 compared with zymosan alone). The monoclonal antibody 5C6, directed against murine CD11b, was injected, 1 mg i.v. 15 min prior to LPS or 15 min before the zymosan, and compared with immunoglobulin G-injected controls. Albumin accumulation was significantly reduced by 5C6 when given prior to the LPS (P<0.01), but not when given before zymosan in the combined LPS and zymosan treatment. Interestingly, albumin accumulation induced by zymosan alone was not reduced by 5C6. The lungs of the mice treated with LPS and zymosan showed a marked, diffuse accumulation of inflammatory cells which, by light microscopy, appeared to be interstitial. Foci of neutrophil aggregates were seen in noncapillary microvessels, and pretreatment with 5C6 appeared to reduce their frequency. In the animals treated with zymosan alone, LPS alone, or LPS and zymosan in combination, electron microscopy established that approximately 25% of all nucleated cells were neutrophils: 99% of the neutrophils were restricted to the intravascular compartment. Pretreatment with 5C6 prior to LPS and zymosan treatment reduced the increase in percentage of neutrophils by half. These results indicate a disassociation between induction of permeability and neutrophil emigration in our murine model and suggest that the release of neutrophil-derived factors such as platelet-activating factor, proteases, or oxidants may be involved.
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PMID:A role for the beta2 integrin CD11b in mediating experimental lung injury in mice. 860 Sep 41

Blood neutrophils contribute to joint injury in human and experimental models of arthritis. Neutrophil migration out of the blood in joint inflammation involves both the CD18 (beta2) integrins and a CD18 integrin-independent pathway. To investigate this migration, radiolabeled rat blood neutrophils were used to measure neutrophil accumulation in the inflamed joints of rats with adjuvant arthritis and the role of leukocyte integrins in migration to these joints and to dermal inflammation was determined. Neutrophils migrated rapidly (<2 h) to the inflamed joints 14-18 d after immunization with adjuvant. Blocking monoclonal antibodies (mAbs) to both LFA-1 and Mac-1 together, as well as a mAb to CD18, inhibited neutrophil accumulation in the inflamed joints by 50-75%. However, migration to dermal inflammation induced by C5a(des Arg)' tumor necrosis factor alpha, lipopolysaccharide, and poly-inosine:cytosine was inhibited by approximately 90%. Flow cytometry revealed the expression of low levels of very late antigen 4 (VLA-4) on nearly all rat blood neutrophils. Treatment with anti-VLA-4 plus anti-LFA-1 but neither mAb alone, strongly (60-75%) inhibited neutrophil accumulation in arthritic joints. This mAb combination also inhibited neutrophil migration to dermal inflammatory reactions by 30-70%. Blocking VLA-4 together with the CD18 integrins inhibited neutrophil accumulation by 95-99%, virtually abolishing neutrophil accumulation in cutaneous inflammation. A similar blockade of VLA-4 and CD18 decreased neutrophil accumulation in the inflamed joints by 70-83%, but a significant portion of the neutrophil accumulation to these joints still remained. In conclusion, rat blood neutrophils express functional VLA-4 that can mediate neutrophil migration to both inflamed joints and dermal inflammatory sites. VLA-4 appears to be able to substitute for LFA-1 in this migration and is particularly important for accumulation in inflamed joints. However, there exists an additional CD18- and VLA-4-independent pathway of neutrophil migration to arthritic joints that is not involved in acute dermal inflammation.
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PMID:Rat blood neutrophils express very late antigen 4 and it mediates migration to arthritic joint and dermal inflammation. 864 27


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