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)

Colony-stimulating factors are growth factors which induce differentiation of the hematopoietic stem cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates proliferation and improves functions of neutrophils and monocyte/macrophages. A macrophage submesothelial stratum has been suggested to constitute the first line of peritoneal defense. We have tested whether intraperitoneally administered GM-CSF could increase the number and activation of peritoneal macrophages in peritoneal dialysis patients. Eight stable patients injected 17 micrograms of GM-CSF in each of their four daily CAPD bags over three days. The clinical status, the peritoneal effluent and peripheral blood cell count, membrane receptor expression, phagocytosis activity and cytokine levels were monitored at days 0, 1, 3, 10 and 28. GM-CSF administration caused a large increase in peritoneal macrophage number (89-fold mean increase after 72 hr), returning to baseline seven days after withdrawal. GM-CSF triggered an increase in the expression of CD11b/CD18 (CR3) and its counterreceptor CD54, indicating the cellular progression into a more activated state. Both the number of phagocytic cells (55 +/- 15% to 83 +/- 10%, P < 0.05) and the phagocytic index (137 +/- 29 to 255 +/- 61, P < 0.01) were also augmented. Peritoneal effluent cytokine-chemokine levels demonstrated an increase in IL-6 and MCP-1 levels while TNF-alpha, IL-1, IL-8, MIP-1 alpha and RANTES were not significantly altered. GM-CSF administration did not affect the peritoneal transport of water or solutes. Minor side-effects were registered in two patients. In conclusion, intraperitoneal GM-CSF causes a marked and transient recruitment of primed macrophages into the peritoneum without inducing inflammatory parameters. GM-CSF should improve the peritoneal defensive capacity through potentiation of the effector functions of resident and newly-recruited macrophages.
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PMID:Immunomodulation of peritoneal macrophages by granulocyte-macrophage colony-stimulating factor in humans. 894 92

To study the mechanisms involved in the movement of neutrophils from the blood stream into the lung airways, we investigated human neutrophil transmigration across a monolayer of human airway epithelial cells, both in the apical-to-basolateral direction and in the more physiologic basolateral-to-apical direction. Migration of human neutrophils across monolayers of human airway epithelial H292 cell-line cells and primary bronchial epithelial cells occured most efficiently in the basolateral-to-apical direction, both after the addition of chemoattractants to resting epithelial cells and across interleukin-1beta (IL-1beta)-stimulated epithelial cells. Blocking studies with monoclonal antibodies revealed that the migration of neutrophils was mediated by the CR3 adhesion molecule (CD11b/CD18) on the neutrophils. IL-1beta-treated epithelial cells caused neutrophil movement via the secretion of chemoattractants. The most potent chemoattractant released by the epithelial cells was found to be IL-8, because the IL-1beta-induced migration was inhibited for 75 +/- 10% by the addition of an antibody against IL-8. After apical stimulation of the epithelial cells with an optimal concentration of IL-1beta, 27 +/- 4 ng/ml IL-8 was found in the supernatant at the apical side of epithelial cells. Platelet-activating factor (PAF) synthesis by the epithelial cells did not play a role in neutrophil transmigration, as was demonstrated by the lack of inhibition of this process after addition of the PAF-receptor antagonist WEB 2086. We conclude that the movement of neutrophils across airway epithelial cell monolayers occurs preferentially in the physiologic basolateral-to-apical direction, indicating that the polarity of epithelial cells is important for neutrophil transmigration.
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PMID:Transmigration of human neutrophils across airway epithelial cell monolayers is preferentially in the physiologic basolateral-to-apical direction. 896 72

Neutrophil emigration through endothelial cells under shear flow involves several adhesion processes including cell rolling, arrest, and transmigration. Rolling is mediated by selectins, while arrest and transmigration both require activated CD18 integrins. One mode of CD18 activation is via selectins expressed on neutrophils and endothelial cells. We have recently reported that cross-linking of L-selectin (CD62L) resulted in the rapid activation of CD18-dependent adhesion. In the current study, we examine whether binding of E-selectin (CD62E) and L-selectin can activate neutrophil CD18-dependent adhesion under shear flow. Human ICAM-1 (CD54) and E-selectin were co-transfected into L cells. Neutrophil capture, rolling, and arrest on these monolayers were quantitated in a parallel plate flow chamber at a wall shear stress of 2.0 dyne/cm2. Under these conditions, E-selectin supported cell capture and rolling on the monolayer, but did not trigger CD18-mediated cell arrest within 200 microm of rolling. However, when neutrophils were treated with anti-L-selectin mAb and cross-linked with a secondary mAb, approximately 50% of the cells arrested within 54 microm. Cell arrest was also observed in response to IL-8 stimulation. A subthreshold level of IL-8 in combination with L-selectin cross-linking potentiated the level of cell arrest due to either stimulus alone. The transition to cell arrest involved both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18). Blocking either subunit alone failed to reduce arrest, while blocking both molecules with mAbs reduced the number to baseline levels. These data support the conclusion that L-selectin, but not E-selectin, can signal the transition from neutrophil rolling to cell arrest under shear flow.
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PMID:Neutrophil CD18-dependent arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow can be activated through L-selectin. 897 12

Tepoxalin, a dual enzyme inhibitor of cyclooxygenase and 5-lipoxygenase has been shown to inhibit T-cell activation. Its immunosuppressive property is distinct from cyclosporin because only tepoxalin, but not cyclosporin, suppresses NF-kappa B activation. Here we report that tepoxalin selectively inhibits intercellular adhesion molecule-1 (ICAM-1, CD54)/MAC-1 (CD11b/CD18) dependent adhesion of polymorphonuclear cells to IL-1 activated human umbilical vein endothelial cells. The mechanism of inhibition is related to the surface expression of several cell adhesion molecules. Flow cytometry analyses on cultured cells that were treated with tepoxalin or antisense oligonucleotides to the P65/p50 subunit of NF-kappa B, and then stimulated with PMA, revealed a reduced expression of CD11b/CD18 on monocytic HL60 cells, and endothelial adhesion molecule-1 (CD62E) and vascular adhesion molecule-1 (CD106) on human umbilical vein endothelial cells. Expression of other adhesion molecules such as lymphocyte function associated-antigen-1 (CD11a/CD18) and CD54 were unaffected. Tepoxalin also inhibited the secretion of a NF-kappa B regulated chemokine, IL-8, a known inducer of CD11b/CD18 expression. Thus the suppression of CD11b/CD18 expression by tepoxalin may involve IL-8. Our results suggest that by inhibiting NF-kappa B activation, surface expression of several adhesion molecules can be modulated and that tepoxalin may be useful in treating selected adhesion mediated events such as leukocyte migration or atherosclerotic plaque formation.
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PMID:The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106. 902 87

We describe a 15-yr-old girl with recurrent bacterial infections who is refractory to the effects of LPS in vivo and in vitro and IL-1 in vitro. Intravenous challenge of the patient with Escherichia coli endotoxin caused a subnormal febrile response, little alteration in the number of circulating neutrophils, and subnormal elevations in the plasma levels of TNF-alpha, IL-6, IL-8, lactoferrin, and granulocyte CSF; however, normal levels of the anti-inflammatory mediators IL-1 receptor antagonist and soluble TNF receptor (60 kDa) were induced. Studies in vitro indicated the patient's monocytes expressed CD14, the LPS receptor, and bound LPS in a specific manner, but failed to produce TNF-alpha and granulocyte CSF after stimulation with LPS, and failed to respond to IL-1, heat-killed Staphylococcus aureus, and soluble glucan. Peripheral blood patient neutrophils exhibited normal expression of CD14, but failed to respond to treatment with LPS (100-1000 ng/ml for 30 min at 37 degrees C), a treatment that caused increased expression of the surface markers, C10, CD18, CD11b, CD67, and CD45, and decreased expression of L-selectin in normal neutrophils. Treatment of normal and patient neutrophils with FMLP (0.1 microM) resulted in equivalent altered expression of these surface markers. Patient neutrophils could not be primed by either LPS or IL-1beta for enhanced FMLP-induced O2- generation, but primed normally to TNF-alpha and platelet-activating factor. This patient's hyporesponsiveness to LPS and IL-1 is most likely due to a defect very early in the signal-transduction pathway.
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PMID:Endotoxin and IL-1 hyporesponsiveness in a patient with recurrent bacterial infections. 910 66

Migration of eosinophils through the basement membrane barrier is an important step for their infiltration into tissues. To investigate the mechanism of transmigration, we used a chamber fitted with a Matrigel membrane as a model of the basement membrane. In this model, eosinophils treated with cytokines or chemotactic factors alone did not transmigrate from the upper to the lower chamber. However, platelet-activating factor (PAF) strongly induced transmigration of eosinophils stimulated by interleukin (IL)-5, indicating that both a cytokine and a chemotactic factor are required for eosinophil migration through Matrigel. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 also stimulated eosinophil transmigration in the presence of PAF. Of seven eosinophil chemotactic factors tested, leukotriene B4, C5a, RANTES, macrophage inflammatory protein-1alpha, and IL-8 did not induce significant eosinophil transmigration. Only PAF and eotaxin induced transmigration of eosinophils through Matrigel in the presence of IL-5; PAF was more potent than eotaxin at the optimal concentration. In contrast, PAF, eotaxin, and RANTES all potently induced migration of eosinophils through bare membrane in the absence of IL-5. Finally, eosinophil migration through Matrigel was markedly reduced by a combination of anti-CD18 and anti-CD29 monoclonal antibodies, suggesting that it is mediated by beta1- and beta2-integrin adhesion molecules. Our findings demonstrate that eosinophil transmigration through a basement membrane model requires both a specific chemoattractant, such as PAF, and an eosinophil-activating cytokine, such as IL-5. This synergistic effect is likely important in the tissue accumulation of activated eosinophils in allergic and other eosinophil-associated diseases.
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PMID:Transmigration of eosinophils through basement membrane components in vitro: synergistic effects of platelet-activating factor and eosinophil-active cytokines. 911 57

We investigated the hypothesis that CD54 (intercellular adhesion molecule-1) expressed on hepatocytes will support beta2-integrin (CD18)-dependent adhesion of neutrophils. An in vitro model using C3A cells (a human hepatoblastoma cell line exhibiting many characteristics of normal hepatocytes) and human neutrophils was utilized. C3A cells were stimulated with interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, or interferon-gamma (IFN-gamma) for 24 h to induce expression of CD54, and adhesion of neutrophils was found to be markedly increased. Detailed studies with IFN-gamma-stimulated (100 U/ml) C3A cells revealed that this adhesion involved CD11a/CD18 [lymphocyte function-associated antigen-1 (LFA-1)] and CD54 and was dependent on low levels of IL-8 produced by the stimulated hepatocytes. Addition of higher concentrations of chemotactic factor (e.g., IL-8) further augmented adhesion and recruited contributions of CD11b/CD18 (Mac-1). In contrast to LFA-1, Mac-1 appeared to recognize a CD54-independent ligand constitutively expressed on the hepatocytes. Such close apposition of neutrophils to hepatocytes may increase the potential for parenchymal cell injury by providing a short distance through which cytotoxic factors such as reactive oxygen or proteolytic enzymes could act.
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PMID:CD18 integrin and CD54-dependent neutrophil adhesion to cytokine-stimulated human hepatocytes. 912 60

The aim of the present study was to investigate the in vivo effects of granulocyte colony-stimulating factor (G-CSF) on neutrophil (PMN) function. G-CSF was administered once daily as s.c. injection for 6 d (d1-6) to healthy male volunteers. PMN migration (modified Boyden chamber), chemiluminescence (CL), adherence to nylon fibers and phagocytosis of IgG- and IgG-C3-coated particles were investigated before (d1), during (d2, d5) and 3 wk after G-CSF 7.5-10 micrograms/kg/d (n = 12). PMN surface expression of adhesion- and Fc gamma-receptors was measured on d1, d5, d8 and 3 wk after G-CSF 3-5 micrograms/kg (n = 12). Results obtained after G-CSF were compared to baseline using Wilcoxon's signed rank test. G-CSF induced PMNs showed a significantly (p < 0.05) decreased chemokinetic response (d5) as well as a reduced chemotaxis towards zymosan activated serum, FMLP and IL-8, respectively. Chemotaxis was reduced both at d2 and d5. Neutrophil adherence, phagocytosis and luminol-enhanced CL increased, whereas G-CSF had no effect on lucigenin-enhanced CL. G-CSF (3-5 micrograms/kg) caused an enhanced expression of CD11b, CD18, CD35, CD64 (Fc gamma RI) and CD32 (Fc gamma RII), respectively. We conclude that neutrophils produced in response to G-CSF have a reduced chemotaxis but an enhanced adherence and phagocytic capacity. G-CSF in vivo does not stimulate the respiratory burst.
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PMID:Effects of in vivo administration of G-CSF on neutrophil functions in healthy volunteers. 915 Jul 14

beta2 integrins (CD11/CD18) play a key role in the adhesion, activation, migration and phagocytosis of human neutrophils. In order to exert their functions, beta2 integrins require activation, which results in an enhancement of ligand affinity. This functional up-regulation is probably due to a conformational change of the beta2 integrins, but the mechanisms of inside-out signaling that trigger this activation are still under investigation. In the present study, the effect of cellular lipids on the affinity state of beta2 integrins was investigated. Lipids were extracted from human neutrophils and HL-60 cells after stimulation with IL-8 or phorbol ester, respectively. The extracts were purified by anion exchange chromatography and/or HPLC fractionation. The lipid extracts induced the adhesion of neutrophils to fibrinogen and, in a cell-free assay system, the binding of C3bi-coated zymosan-particles by purified beta2 integrin Mac-1 (CD11b/CD18). The integrin up-regulating activity was resistant to ester hydrolysis, eluted as one particular HPLC-fraction, and showed an absorption maximum at 194+/-2 nm. Taken together, these data support the concept that activated neutrophils and HL-60 cells can generate an endogenous lipid mediator, which up-regulates ligand binding activity of beta2 integrins.
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PMID:Activation of the beta2 integrin Mac-1 (CD11b/CD18) by an endogenous lipid mediator of human neutrophils and HL-60 cells. 915 24

Coagulation and fibrinolysis universally accompany tissue injury and repair. The accumulation of regionally generated fibrin degradation products (FDP) may modify the local inflammatory response. We have found FDP to be potent neutrophil chemotaxins. We separated plasmin FDP by chromatofocusing and found chemotactic activity limited to fractions containing the fibrinogen D domain (D-D dimer and D monomer). The bioactivity of the D-D dimer did not require an intact cross link site as removal of this sequence with puff adder venom or hypocalcemic plasmic digestion did not decrease chemotaxis. Peptide inhibition studies confirmed that the chemotactic region did not involve terminal gamma chain sequences or alpha chain RGD motifs. The internal gamma chain peptide KYGWTVFQKRLDGSV (P1), known to bind CD11b/CD18, exhibited concentration dependent chemotactic activity. Similarly, monoclonal antibodies directed against CD11b/CD18 blocked PMN migration to FDP without similar inhibition of chemotaxis to IL-8 or LTB4. Thus, neutrophil chemotaxis to FDP is mediated by interactions between the fibrinogen D domain and CD11b/CD18.
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PMID:CD11b/CD18 mediates the neutrophil chemotactic activity of fibrin degradation product D domain. 918 99


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