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)

Isolation of the human neutrophil activating protein (NAP) interleukin 8 (IL8) from leukocytes has revealed that it is structurally related to beta-thromboglobulin (beta TG) from platelets. Both these proteins occur as natural mixtures of multiple forms, differing from each other by unequal truncation at the NH2 terminus. In this study we have compared IL8 and beta TG forms for in vitro and in vivo neutrophil activation. In contrast to IL8, none of the beta TG forms were found to exert granulocyte chemotactic activity in vitro, as measured in the agarose assay. However, fractions rich in the most extensively processed forms of beta TG (e.g. NAP-2) as well as pure NAP-2 did induce lactoferrin release from granulocytes, whereas fractions containing only the longer forms (e.g. connective tissue-activating peptide III) were inactive. In order to observe this in vitro effect, about 10-fold less IL8 (10 nM) than NAP-2 was required. In the presence of a vasodilator substance low doses (2-20 pmol) of IL8 and the shorter forms of beta TG caused granulocyte accumulation and plasma leakage in rabbit skin whereas the longer forms of beta TG again failed to do so. Finally, granulocytosis induction following i.v. injection was found to occur with NAP-2. At the maximal dose tested (250 pmol), this in vivo effect of NAP-2 was less pronounced than that of IL8. In the case of IL8, NH2-terminal processing did not seem to affect granulocyte stimulatory activity. It should be noted, however, that the extent of processing of IL8 is less than that occurring with beta TG. It can be concluded that the platelet factor beta TG, structurally related to the monokine IL8, can also play a role in neutrophil activation during inflammatory reactions.
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PMID:The neutrophil-activating proteins interleukin 8 and beta-thromboglobulin: in vitro and in vivo comparison of NH2-terminally processed forms. 214 75

The influence of human monocyte-derived chemotactic peptide (GCP/IL-8) on degranulation of neutrophils was investigated in relation to that of other monokines. GCP/IL-8 promoted a dose-dependent release of lactoferrin from specific granules but had no effect on enzyme release from primary granules. From the other monokines that were tested, tumour necrosis factor alpha (TNF alpha) also induced degranulation, while IL-1 beta and IL-6 scored negatively. TNF alpha-induced lactoferrin release was enhanced by cytochalasin B pretreatment of the granulocytes, while GCP/IL-8-promoted degranulation was not. In contrast to GCP, TNF alpha also caused the release of LDH, suggesting a non-specific cell destruction. These observations further support the view that, unlike the other monokines, GCP/IL-8 is a true and specific granulocyte activator.
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PMID:Human granulocyte chemotactic peptide (IL-8) as a specific neutrophil degranulator: comparison with other monokines. 267 Jul 52

Intravenous administration of endotoxin into humans causes transient fever, alteration in the number of circulating neutrophils, and transient release into plasma of cytokines, cytokine antagonists, and other cellular products. The release can be temporally differentiated, and the extent of release is dose-dependent. By 1 h after endotoxin challenge, levels of tumor necrosis factor (TNF)-alpha and soluble TNF receptor increase; interleukin (IL)-6 and IL-8 increase by 1.5 h, and IL-1 receptor antagonist, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, and lactoferrin increase by 2 h. Increased G-CSF is temporally associated with neutrophilia and the appearance of band neutrophils. Increased plasma lactoferrin and altered neutrophil surface antigen expression suggest that intravascular activation of neutrophils has occurred. The level of soluble E-selectin (sE-sel), an adhesion molecule released from endothelial cells, is elevated at 4 h and remains elevated at 24 h. sE-sel levels increase with higher doses of endotoxin at 4, 6, and 24 h.
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PMID:Increased circulating cytokines, cytokine antagonists, and E-selectin after intravenous administration of endotoxin in humans. 752 50

TNF is considered to be an intermediate factor in endotoxin-induced release of other cytokines and endotoxin-induced neutrophil degranulation. Little is known about the effect of postponed treatment with anti-TNF in primate endotoxin models. To assess the effect of delayed treatment with anti-TNF in endotoxaemia, six healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin (4 ng/kg). In three of these animals the administration of endotoxin was followed after 30 min by a bolus i.v. injection of the anti-TNF F(ab')2 fragment MAK 195F (0.1 mg/kg). Post-treatment with MAK 195F completely prevented the appearance of TNF activity in serum elicited by endotoxin, and markedly reduced the rises in the serum concentrations of IL-6 and IL-8. In addition, the endotoxin-induced increases in the type I and type II soluble TNF receptors were also profoundly inhibited by MAK 195F, suggesting that TNF is involved in the release of its own soluble receptors in endotoxaemia. Neutrophilic leucocytosis was not affected by MAK 195F. In contrast, MAK 195F did significantly abrogate neutrophil degranulation, as measured by the plasma concentrations of lactoferrin. These results indicate that treatment with anti-TNF 30 min after the administration of endotoxin is still effective in attenuating the induction of the cytokine network and of neutrophil degranulation.
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PMID:Effect of postponed treatment with an anti-tumour necrosis factor (TNF) F(ab')2 fragment on endotoxin-induced cytokine and neutrophil responses in chimpanzees. 769 17

Cells infiltrating the nonsensory epithelium of the vomeronasal organ of virus-antibody-free rats exhibited surface immunoreactivity for beta 2-microglobulin and immunoglobulin (Ig) E. They were further characterized by using immunohistochemical techniques with antibodies to cell-specific markers or histochemical techniques for immunocytes with surface receptors for IgE. Localization of intracellular granules immunoreactive for lactoferrin and CD18, a leukocyte adhesion molecule, unequivocally identified these cells as neutrophils. The low number of IgA- and IgG-immunoreactive B lymphocytes, T lymphocytes, and accessory immunocytes in the vomeronasal organ as well as the rest of the nasal cavity confirmed the absence of infection. We hypothesize that the operation of the vomeronasal pump induces repeated episodes of transient focal ischemia followed by reperfusion, which results in release of neutrophil chemoattractants and modulation of adhesion factors that regulate the extravasation and migration of neutrophils into the nonsensory epithelium. The distribution of immunoreactivity for interleukin 8 suggests that it is not the primary neutrophil chemoattractant in this system while that of CD18 suggests its active involvement in neutrophil extravasation. In addition to their role in immune surveillance, neutrophils may stimulate ion/water secretion into the vomeronasal lumen, affecting the perireceptor processes regulating stimulus access and clearance from the sensory epithelium.
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PMID:Identification of neutrophils in the nonsensory epithelium of the vomeronasal organ in virus-antibody-free rats. 775 Jan 29

To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.
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PMID:Inhibition of endotoxin-induced cytokine release and neutrophil activation in humans by use of recombinant bactericidal/permeability-increasing protein. 779 4

Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxifylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in combination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for measurements of leukocyte counts and the granulocytic proteinases elastase complexed with alpha 1-antitrypsin and lactoferrin, and cytokines during the next 5 h. No changes were observed in the saline-treated chimpanzees. Endotoxin induced a marked leukocytosis and neutrophilia, which were slightly reduced by pentoxifylline. In contrast, pentoxifylline almost completely prevented endotoxin-induced neutrophil degranulation: peak elastase-alpha 1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentoxifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inhibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 pg/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml at t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system could be detected. We conclude that pentoxifylline attenuates neutrophil activation in endotoxemia in chimpanzees, probably in part by inhibiting the release of TNF.
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PMID:Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees. 834 9

Platelet factor 4 (PF-4), like IL-8, is a member of the chemokine superfamily of proinflammatory cytokines. However, although the capacity of IL-8 to stimulate functions in neutrophils is well established, reports on PF-4 are still contradictory. In the present study, we have prepared highly purified PF-4 and examined its ability to induce chemotaxis, degranulation, adhesion to gelatin and plasma proteins, and changes in intracellular calcium levels. Even over a broad range of concentrations, PF-4 alone was unable to induce functional changes in PMN. However, neutrophils pre- or co-incubated with physiologically relevant concentrations of TNF-alpha responded to PF-4 by the selective mobilization of the secondary granule marker lactoferrin but not of the primary granule marker elastase. Contrary to IL-8, PMN did not require pretreatment with cytochalasin B for PF-4-induced exocytosis of lactoferrin. The synergistic effect of PF-4 with TNF-alpha was not a priming phenomenon because the cooperative response remained unchanged even when TNF-alpha was added 5 min after the chemokine. In contrast, TNF-alpha-treated PMN did not respond to PF-4 by chemotaxis or by an increase of intracellular calcium levels, and no competition of PF-4 for IL-8 receptors was observed. Our results suggest a mechanism as well as a biologic role of PF-4 in the regulation of neutrophil function, which is different from that of IL-8 and other alpha-chemokines.
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PMID:TNF-alpha renders human neutrophils responsive to platelet factor 4. Comparison of PF-4 and IL-8 reveals different activity profiles of the two chemokines. 859 50

The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.
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PMID:IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer. 859 89

Granulocyte colony-stimulating factor (G-CSF) was administered at a dose of 7.5 or 10 micrograms/kg s.c. once daily for 6d (days 1-6) to two groups consisting of eight and six healthy volunteers. The administration of G-CSF resulted in a rapid decrease in neutrophil counts and serum levels of the secondary granule protein, human neutrophil lipocalin (HNL) after 30 min, followed by a recovery and gradual increase within 180 min. The number of circulating neutrophils and plasma and serum levels of neutrophil secondary granule proteins were dramatically elevated on day 2 (1 d after the administration of G-CSF) and stayed so until day 7. The plasma levels of HNL and lactoferrin (LF) showed a biphasic pattern with peaks at day 2 and days 5-7, and remained highly elevated at day 12. The serum levels of HNL and LF increased rapidly (about 8-fold and 6-fold, respectively) on day 2 and stayed elevated until day 7, subsequently returning to baseline levels. At day 5, neutrophil release induced in vitro by f-MLP was significantly enhanced. The cellular contents of HNL and LF were reduced to about 50% of levels before G-CSF administration at day 5. The release of lactoferrin and HNL, but not of myeloperoxidase (MPO), was slightly enhanced after preincubation of isolated normal neutrophils with G-CSF in vitro, but no obvious release of these proteins was observed with G-CSF alone. The administration of G-CSF resulted in a dramatic increase in the alkaline phosphatase (AP) activity in the plasma membrane, with maximal activity occurring at day 5. Furthermore, during administration of G-CSF, TNF-alpha in plasma increased about 25-fold. TNF-alpha started to rise at day 2 and peaked at day 6. After discontinuation of G-CSF the levels of TNF-alpha gradually decreased. The elevated levels of TNF-alpha (tumour necrosis factor-alpha) were temporally correlated to the other signs of neutrophil activation. GM-CSF and IL-8, however, were not detected in plasma. Our data suggest that G-CSF affects the neutrophils not only directly but also indirectly by the induction of the production of other cytokines such as TNF-alpha.
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PMID:The effect of granulocyte colony-stimulating factor (G-CSF) on the degranulation of secondary granule proteins from human neutrophils in vivo may be indirect. 865 73


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