Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kinetics of the response of integrins to activating signal(s) must be rapid to ensure that rolling neutrophils are localized at the sites of inflammation. From video records, we analyzed the adhesion of individual neutrophils in a flow-based in vitro model of endothelial hypoxia and reoxygenation. There were numerous rolling interactions between flowing neutrophils and P-selectin on human umbilical vein endothelial cells after hypoxia, but 90% lasted for < 1 s, with approximately 30% converted to stationary attachment via beta 2-integrin(s). Interleukin-8 (IL-8) and platelet-activating factor (PAF) were responsible for neutrophil activation in this model [G. E Rainger, A. Fisher, C. Shearman, and G. B. Nash. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1398-H1406, 1995]. In the presence of a PAF-receptor antagonist, IL-8 acting alone induced conversion of rolling to stationary adhesion in as little as 80 ms after the initial attachment of a neutrophil, with a median response time of 240 ms. In the presence of a monoclonal antibody that neutralized IL-8 activity, PAF acting alone required a minimum duration of rolling of 560 ms to promote stationary adhesion, with a significantly longer median duration of 720 ms. In a reconstituted model, treatment of endothelial cells with hydrogen peroxide induced short-lived rolling of neutrophils supported by P-selectin. Exogenously added IL-8 and/or PAF bound to the endothelial surface and successfully induced the immobilization of neutrophils. Rapid and distinct kinetics of the conversion to stationary adhesion were observed again for IL-8 or PAF. Thus although endothelial-presented signals differed in their rate of action, neutrophils could be localized within one or two endothelial cell diameters of their initial adhesive contact point.
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PMID:Endothelial-borne platelet-activating factor and interleukin-8 rapidly immobilize rolling neutrophils. 903 29

The activation of endothelial cells is a recurrent phenomenon linked to pathologic conditions such as inflammation, chronic arthritis, allo- and xenograft rejection. To inhibit endothelial cell activation we have constructed a transactivation-deficient derivative of the p65/RelA subunit of NF-kappa B, a transcription factor known to be crucial for the induction of adhesion molecules, cytokines and procoagulants in activated endothelial cells. This protein (p65RHD) comprises the Rel homology domain of the RelA subunit, retaining dimerization, DNA binding, and nuclear localization functions, but is deficient in transcriptional activation, and acts as a competitive inhibitor of NF-kappa B. Our data demonstrate that p65RHD is a potent and specific inhibitor of NF-kappa B-mediated induction of a number of genes, such as I kappa B alpha, IL-8, E-selectin, P-selectin, and tissue factor in endothelial cells. Furthermore, tetracycline-inducible expression of p65RHD in stably transfected primary endothelial cells inhibits the induction of gene expression equally well. This regulated system of gene expression provides the basis for a novel therapeutic approach to the pathologic effects of endothelial cell activation, especially in delayed xenograft rejection, by using transgenic animals as organ donors.
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PMID:Inhibition of bovine endothelial cell activation in vitro by regulated expression of a transdominant inhibitor of NF-kappa B. 904 81

In addition to its role in coagulation, thrombin is involved in the inflammatory process by inducing vessel neutrophilic infiltration. Thrombin induces endothelial P-selectin expression and platelet activating factor release, which participate to induce early neutrophil adhesion and activation. We employed HUVEC and now show that thrombin induces the production of the chemokine IL-8 in a time- and dose-dependent fashion. Similarly, thrombin induced E-selectin expression on HUVEC. Both IL-8 secretion and E-selectin expression were preceded by an increase in steady state levels of the respective mRNAs. Thrombin action on HUVEC was inhibited by the specific thrombin inhibitor, hirudin. In addition, these effects of thrombin on HUVEC were mimicked by the 14-amino acid thrombin receptor agonist peptide, which triggers the native thrombin receptor in a similar fashion to thrombin itself. Although IL-1 and TNF-alpha also induce IL-8 and E-selectin, the thrombin effects in these experiments were not mediated by those cytokines, since neither IL-1 receptor antagonist nor anti-TNF-alpha Ab inhibited the effects of thrombin. Furthermore, IL-1alpha, IL-1beta, and TNF-alpha were not detected in the supernatants of thrombin-activated HUVEC. Although intracellular IL-1alpha was found in thrombin-activated HUVEC, antisense IL-1alpha had no inhibitory effect on IL-8 secretion. These results demonstrate that in addition to short term endothelial activation, thrombin also functions as a long acting proinflammatory agent by inducing endothelial synthesis of the mediators required for neutrophils activation and extravazation during inflammation.
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PMID:Thrombin induces endothelial type II activation in vitro: IL-1 and TNF-alpha-independent IL-8 secretion and E-selectin expression. 916 65

Oncostatin M is a member of the IL-6 family of cytokines that is primarily known for its effects on cell growth. Endothelial cells have an abundance of receptors for oncostatin M, and may be its primary target. We determined if oncostatin M induces a key endothelial cell function, initiation of the inflammatory response. We found that subcutaneous injection of oncostatin M in mice caused an acute inflammatory reaction. Oncostatin M in vitro stimulated: (a) polymorphonuclear leukocyte (PMN) transmigration through confluent monolayers of primary human endothelial cells; (b) biphasic PMN adhesion through rapid P-selectin expression, and delayed adhesion mediated by E-selectin synthesis; (c) intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 accumulation; and (d) the expression of PMN activators IL-6, epithelial neutrophil activating peptide-78, growth-related cytokine alpha and growth-related cytokine beta without concomitant IL-8 synthesis. The nature of the response to oncostatin M varied with concentration, suggesting high and low affinity oncostatin M receptors independently stimulated specific responses. Immunohistochemistry showed that macrophage-like cells infiltrating human aortic aneurysms expressed oncostatin M, so it is present during a chronic inflammatory reaction. Therefore, oncostatin M, but not other IL-6 family members, fulfills Koch's postulates as an inflammatory mediator. Since its effects on endothelial cells differ significantly from established mediators like TNFalpha, it may uniquely contribute to the inflammatory cycle.
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PMID:Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. 920 68

Rheumatoid arthritis (RA) is a chronic, aggressive disease characterized by inflammatory cells in the synovial tissue (ST) and synovial fluid (SF). Interleukin (IL)-13 inhibits the production of proinflammatory cytokines, chemokines, and hematopoietic growth factors by activated human monocytes. The aim of this study was to determine the production of IL-13 in various forms of arthritis. The presence of IL-13 in RA was found to be low, in that 18 of 26 RA SF samples and 10 of 14 RA peripheral blood (PB) samples had nondetectable levels (</=12 pg/ml). Similar low levels were found in SF and PB from patients with osteoarthritis (OA) and other arthritides. In contrast, RANTES, IL-8, monocyte chemotactic protein-1, and soluble P-selectin were found at levels of 13-, 120-, 1200-, and 2000-fold excess of IL-13, respectively. Mononuclear cells isolated from RA SFs did not produce significant levels of IL-13 in culture (</=12 pg/ml) but were able to do so when stimulated with phytohemagglutinin. Likewise, tissue explants from RA synovium cultured for 24 or 48 hr with or without serum did not produce appreciable quantities of IL-13 (</=12 pg/ml). Immunohistochemical data were in accordance with this result in that antigenic IL-13 was not detected on the majority of RA, OA, and normal (NL) ST cells. These results demonstrate a paucity of IL-13 within the joints of RA, OA, NL, and other arthritic patients by comparison with levels of other cytokines.
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PMID:Low-level production of interleukin-13 in synovial fluid and tissue from patients with arthritis. 934 5

By extrapolation from the responses of cultured human umbilical vein endothelial cells (EC) and bovine aortic EC to short-term cytokine stimulation, EC activation is postulated as a likely component of the host response in acute allograft rejection and cardiac transplant-associated accelerated arteriosclerosis. To investigate the extent to which EC activation occurs in vivo in humans and to identify potential targets for therapeutic interventions, we compared the phenotypic characteristics of vascular EC as seen during clinicopathologically significant vs non-significant acute cardiac allograft rejection. We used monoclonal and monospecific polyclonal antibodies to coagulation molecules [tissue factor, thrombomodulin (TM), antithrombin III (AT-III), fibrinogen/fibrin, cross-linked fibrin and von Willebrand factor (vWF)], adhesion molecules (P-selectin, ICAM-1) and major histocompatibility complex (MHC) class I and II molecules. In addition we sought evidence of local cytokine production (IL-1, IL-2R, IL-4, IL-6, IL-7, IL-8, TNF-alpha, PDGF-AA, PDGF-BB), which might mediate alterations in expression of these proteins. We found that in clinically significant grades of cardiac allograft rejection requiring increased immunosuppression, in contrast to lesser grades of rejection not requiring clinical intervention, there was increased microvascular EC activation and differential expression of cytokines. EC changes associated with more extensive cardiac allograft rejection requiring treatment included: (i) disruption of the normal anticoagulant state with downregulation of TM and AT-III, upregulation of tissue factor and vWF expression, and associated extensive fibrin deposition; (ii) upregulation of MHC class I antigens, which are potential targets for host cytotoxic T lymphocytes; (iii) increased expression of the leucocyte adhesion molecules P-selectin and ICAM-1; (iv) expression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha; and (v) increased expression of PDGF-AA and BB, which are known to promote migration and proliferation of intimal cells, and hence may contribute to development of transplant-associated atherosclerosis. Collectively these findings suggest that immune events resulting in EC surface changes and/or production of key cytokines play a role in the pathogenesis of acute transplant rejection and may contribute to the long-term complication of accelerated arteriosclerosis in allograft coronary arteries.
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PMID:Endothelial activation and cytokine expression in human acute cardiac allograft rejection. 953 4

While it is clear that the clinical expression of IgE-mediated diseases depends upon the actions of multiple mediators, histamine, the earliest recognized mediator of allergy, remains a prominent contributor. Histamine released from mast cells binds to specific receptors (H1, H2, H3) to produce its clinical effects. The cardinal features of asthma include smooth muscle spasm, mucosal edema, inflammation and mucus secretion. It has been demonstrated that two of these features, bronchospasm and mucosal edema, can be caused by H1-receptor stimulation, while H2- and possibly H1-activation are probably minor causes of mucus secretion. Histamine interacts directly with the endothelial cells (EC) and induces permeability, a transient expression of P-selectin and the secretion of lipid mediators (e.g. PGI2, PAF and LTB4). Moreover, histamine induces a significant increase of IL-6 and IL-8 secretion by EC. Since IL-8 exerts a chemotactic activity for neutrophils, eosinophils and basophils, and IL-6 is involved in endothelium permeability, the secretion of cytokines may be involved in the late phase reaction. Some antihistamines (i.e., levocabastine, terfenadine, loratadine, azelastine and oxatomide) can reduce ICAM-1 expression. The participation of histamine in the allergic inflammation, including asthma, must be re-examined, since the effects of histamine are more widespread.
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PMID:[Histamine in the pathogenesis of asthma]. 961 6

Neutrophil degranulation is an important event in inflammatory responses. We examined the regulation of neutrophil (PMN) degranulation by resting and activated human endothelial cells. Whereas PMNs adherent to endothelial cells that were stimulated to express P-selectin and platelet-activating factor did not release the specific granule marker lactoferrin or the primary granule enzyme, elastase, PMNs adherent to endothelial cells stimulated with interleukin-1 (IL-1) or tumor necrosis factor secreted both. PMN degranulation was dependent on the time of incubation of endothelial cells with the cytokine, its concentration, and the time of incubation of the PMNs with endothelial cells. Degranulation of PMNs and their adhesion to stimulated endothelial cells are correlated events, but they could be dissociated by blocking the tethering molecules used by the endothelial cells and neutrophils under these conditions. This suggested that paracrine signaling molecules that induce PMN degranulation are produced by cytokine-stimulated endothelial cells. We found that endothelial cells stimulated with IL-1 release newly synthesized degranulating factors that require transcription and translation. IL-8 was synthesized, released, and signaled granular secretion by PMNs. However, experiments with blocking antibodies indicated the presence of an additional degranulating factor not accounted for by IL-8. These experiments demonstrate that human endothelial cells regulate degranulation of neutrophils by generating signaling factors that are expressed differentially depending on the endothelial agonist and other features. Active modification of neutrophil granular secretion by endothelial cells can influence physiologic acute inflammatory responses but may also contribute to pathologic vascular and tissue damage.
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PMID:Human endothelial cells regulate polymorphonuclear leukocyte degranulation. 961 52

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.
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PMID:Effects of 0.2 ppm ozone on biomarkers of inflammation in bronchoalveolar lavage fluid and bronchial mucosa of healthy subjects. 965 69

Precise assessment of blood cell kinetics in the pulmonary microcirculation is extremely difficult because pulmonary microvascular architecture contains arterioles, venules and capillaries in an exceedingly intricate and densely convoluted fashion. Conventional epiluminescence microscopy may not be suitable for investigation of blood cell kinetic in the pulmonary microcirculation, in which arterioles, venules and capillary networks are not located in the same plane. To overcome these impediments, we recently developed a real-time confocal laser luminescence microscope with a high-speed analysis component having the capacity to yield confocal-images of rapidly moving cells at a rate of 1,000 frames/sec and at sufficiently high magnification. In the current review, we will first introduce the details of our newly developed observation system constructed with a view to estimation of blood cell dynamics in the intraacinar microcirculation of the lung. Applying this novel method to isolated perfused rat lungs, we will secondly address the issue of whether or not leukocyte-endothelium interactions in the pulmonary microcirculation qualitatively differ from those serving in the systemic microcirculation. We will particularly shed light on possible roles of endothelial ICAM-1, endothelial P-selectin and leukocyte L-selectin in distorting leukocyte kinetics in the intraacinar microvessels under a variety of diseased conditions, including prolonged exposure to a hyperoxic environment inducing a significant upregulation of ICAM-1 as well as P-selectin on the pulmonary microvascular endothelium, and stimulation of leukocytes by an IL-8 analog causing downregulation of leukocyte L-selectin but inverse upregulation of CD18-related integrins.
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PMID:Do adhesion molecules importantly regulate leukocyte kinetics within intraacinar microvessels of the lung? 981 May 5


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