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

Thrombin stimulation of human platelets results in the release of a preformed proteinaceous human eosinophil (Eo)-chemotactic activity. By the use of different high-performance liquid chromatography techniques, two Eo-chemotactic polypeptides (EoCPs), tentatively termed EoCP-1 and EoCP-2, were purified to homogeneity. Upon SDS-PAGE analysis, these chemotaxins showed molecular masses near 8 kD. NH2-terminal amino acid sequence analysis revealed identical sequences for both EoCP-1 and EoCP-2, which are also identical to that of RANTES, a cytokine that structurally belongs to the interleukin 8 superfamily of leukocyte selective attractants, and that is known to be a "memory-type" T lymphocyte-selective attractant. In the major Eo chemotaxin, EoCP-1, the residues 4 and 5, which in EoCP-2 were found to be serine residues, could not be identified. Electrospray mass spectrometry (ESP-MS) of EoCPs revealed for EoCP-2 a molecular mass of 7,862.8 +/- 1.1 daltons, which is 15.8 mass units higher than the calculated value of RANTES, indicating that EoCP-2 is identical to the full-length cytokine, and oxygenation, probably at methionine residue number 64, has taken place. Upon ESP-MS, EoCP-1 showed an average molecular mass of 8,355 +/- 10 daltons, suggesting O-glycosylation at these serine residues. Both natural forms of RANTES showed strong Eo-chemotactic activity (ED50 = 2 nM) with optimal chemotactic migration at concentrations near 10 nM, however, there were no significant migratory responses with human neutrophils. Chemotactic activity of RANTES for human Eos could be confirmed using recombinant material, which has been found to be as active as the natural forms. Since RANTES gene expression has been detected in activated T lymphocytes, and recombinant RANTES was shown to be a "memory" T lymphocyte-selective attractant, it is now tempting to speculate about an important role of RANTES in clinical situations such as allergene-induced late-phase skin reactions in atopic subjects or asthma, where in affected tissues both memory T cells and Eos are characteristic.
 ...
PMID:Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. 138 64

The generation of arachidonic acid-derived inflammatory mediators from unstimulated and stimulated neutrophils (PMN) and platelets in the presence of exogenous LTA4 has been studied in patients with atopic dermatitis (AD) as well as in healthy volunteers. PMN were stimulated with the interleukins IL-3, IL-8, C5a, and the Ca-ionophore A23187. In addition, NaF and thrombin were used to stimulate platelets. The release of leukotriene (LT)B4, 20-COOH- and 20-OH-LTB4, cysteinyl-leukotrienes and 12-HETE was measured. The proinflammatory mediator release from PMN and platelets of patients with AD was significantly higher as compared to the control group. The spontaneous conversion of LTA4 by PMN and platelets was markedly enhanced in patients with AD. Different results with receptor-specific and non-specific stimuli (Ca-ionophore A23187) in the presence of exogenous LTA4 were obtained. The results indicate a higher state of activation for enzymes involved in leukotriene formation. Furthermore, the production of 12-HETE by platelets from patients with AD was enhanced in unstimulated and stimulated cells. Our data emphasize that neutrophils and platelets may play an important role in the pathogenesis of AD by an increased responsiveness to receptor-specific stimuli and cell-cell interaction via LTA4.
 ...
PMID:Conversion of leukotriene A4 by neutrophils and platelets from patients with atopic dermatitis. 166 16

We have recently shown that endothelial cell-derived IL-8 inhibits neutrophil adhesion to IL1-beta-activated human umbilical vein endothelial cell monolayers. IL-8 secreted by T lymphocytes or monocytes has been characterized as a promoter of neutrophil degranulation and chemotaxis. The IL-8 isolated from each of these cell types is a mixture of two IL-8 polypeptides, one consisting of 72 amino acids (herein called [ser-IL-8]72) and the other 77 amino acids (an N-terminal extended form herein called [ala-IL-8]77). IL-8 derived from T lymphocytes and monocytes is predominantly [ser-IL-8]72, whereas endothelial-derived IL-8 is highly enriched (greater than 80%) in [ala-IL-8]77. We address the relationship and activities of these two forms of IL-8 using recombinant proteins expressed by both mammalian cells and Escherichia coli. Thrombin was found to efficiently convert [ala-IL-8]77 to [ser-IL-8]72. In contrast, urokinase and tissue-type plasminogen activator were unable to cleave [ala-IL-8]77, and trypsin generated multiple IL-8 cleavage fragments. In competitive binding assays using 125I[ala-IL-8]77 neutrophils exhibited a twofold preference for [ser-IL-8]72 over [ala-IL-8]77. Both forms of IL-8 inhibited neutrophil adhesion to IL-1-beta-activated HUVEC monolayers by up to 90%. However, [ser-IL-8]72 was approximately 10-fold more potent than [ala-IL-8]77 in these assays (ED50 approximately 0.3 nM for [ser-IL-8]72 vs approximately 3 nM for [ala-IL-8]77. Both forms of IL-8 promoted degranulation of cytochalasin B-treated neutrophils [[ser-IL-8]72 (ED50 greater than 10 nM) was two- to three-fold more potent than [ala-IL-8]77], although in this regard they were less active than FMLP. Our data suggest that [ala-IL-8]77 and [ser-IL-8]72 have qualitatively similar and potentially complex biological activities, and that full activation of IL-8 requires cleavage to the [ser-IL-8]72 form. In the case of inflamed endothelial cells this activation could be mediated by thrombin generated in the procoagulant environment associated with these cells.
 ...
PMID:Endothelial and leukocyte forms of IL-8. Conversion by thrombin and interactions with neutrophils. 221 72

The human alveolar macrophage product, enzyme-releasing peptide (ERP), has a molecular mass of 8,000 Da, and releases azurophilic and specific granule constituents from neutrophils. A murine monoclonal anti-ERP antibody (12E10H), previously used to show a lack of antigenic identity between ERP and C5a, interleukin 1, tumor necrosis factor, and gamma-interferon, showed no cross-reactivity with interleukin 8. 12E10H and a fluorescein-labeled second antibody were used to visualize ERP on the macrophage surface. ERP was removed from alveolar macrophages by a 3-min incubation with 5 X 10(-7) M bovine pancreatic trypsin at 37 degrees C. The washed trypsinized cells could readhere to plastic and exclude trypan blue. Dilution of the trypsin-derived ERP released myeloperoxidase from cytochalasin-B-treated neutrophils dose dependently. The enzyme-releasing ability of the trypsin-derived material was removed by immunoprecipitation using antibody 12E10H bound to Staphylococcal protein A Sepharose 4B. The estimated molecular mass of the trypsin-derived ERP (by molecular sieve chromatography on HPLC) was approximately 8,500 Da. Other proteases (plasmin, thrombin, and cathepsin G) also released ERP from the cell surface, but the ERP was not an active secretagogue for neutrophils. However, macrophages cultured with protease inhibitors did not show decreased ERP accumulation in the medium. Our data indicate that ERP exists on the surface of human alveolar macrophages and can be released by proteases found within the lung environment in some disease states.
 ...
PMID:Liberation of a neutrophil enzyme-releasing peptide from the surface of human alveolar macrophages. 236 Jun 46

TNF is a strong secretagogue for surface-contacting neutrophils. During inflammation, endothelium offers the first substrate for neutrophil adherence and for modulation of the toxic response of neutrophils to soluble agonists such as TNF. In this in vitro study, evidence is presented that endothelium participates actively in TNF-induced neutrophil respiratory burst activity by expressing platelet-activating factor (PAF) in response to initial neutrophil H2O2 release. Three findings are shown that favor such a mechanism. First, PAF receptor antagonists reduced H2O2 release by TNF-activated neutrophils placed on endothelium approximately by 50%, whereas H2O2 responses by neutrophils placed on serum-coated polystyrene remained intact. Second, preincubation of HUVEC with known PAF-inducing agents PMA, H2O2, and thrombin, followed by fixation, enhanced neutrophil H2O2 release in response to TNF. H2O2 release by these neutrophils was sensitive to the presence of PAF receptor antagonists, whereas H2O2-release from neutrophils placed on fixed nonactivated endothelial cells was not. Finally, replacing endothelium by monolayers of human renal cortical epithelial cells and human fibroblasts, cells that are known to produce less PAF than endothelial cells, reduced the effect of PAF receptor antagonists. P-selectin expression and IL-8 release, two other ways by which endothelial cells might influence H2O2-release by TNF preincubated neutrophils, were examined in parallel, and were found not to influence TNF-induced neutrophil H2O2-release. We conclude that during neutrophil-endothelial interaction in inflammation, endothelium modulates the toxic response of neutrophils to TNF. Endothelial cell-associated PAF, but not endothelial cell IL-8 release and P-selectin expression, is likely to participate in TNF-induced neutrophil respiratory burst activity.
 ...
PMID:Endothelial cell associated platelet-activating factor (PAF), a costimulatory intermediate in TNF-alpha-induced H2O2 release by adherent neutrophil leukocytes. 752 2

Fibrosis of the pulmonary parenchyma is a frequent and serious complication of scleroderma (systemic sclerosis, SSc), resulting in significant morbidity and mortality. During the past decade data have accumulated in support of an inflammatory process affecting the alveoli and distal airways that culminates in irreversible fibrosis in many SSc patients. Recent findings indicate the presence of lung fibroblasts with altered phenotype and biologic activity (myofibroblasts), perhaps arising from the influence of cytokines on resident lung fibroblasts. Acute-phase inflammatory cytokines such as IL-1 alpha, TNF-alpha, MIP-1 alpha, IL-8 and RANTES are increased in SSc bronchoalveolar lavage (BAL) fluid, as is thrombin, a potent mitogen for lung fibroblasts. Chronic-phase inflammatory and fibrogenic cytokines such as PDGF and TGF-beta are also present in increased amounts in SSc BAL fluid. The inciting event(s) and the process(es) leading to the perpetuation of fibrosis in SSc are unknown. Treatment of SSc lung disease has been empiric and generally disappointing, and it is likely that effective treatment awaits a better understanding of the biological events that regulate collagen and other extracellular matrix synthesis.
 ...
PMID:Interstitial lung disease of systemic sclerosis. 765 Apr 24

The molecular cloning of the C5a receptor places this molecule in the superfamily of G-protein coupled receptors. This superfamily is characterized by the presence of signature motifs including seven hydrophobic domains which span the cell membrane and impart a predicted serpentine topology to the receptor proteins. The identification of other members of this family, including receptors for the chemokines IL-8 and Mip-1/Rantes, thrombin, formyl peptide, and platelet activating factor, provide new tools for understanding structure-function relationships relevant to the inflammatory process. This review focuses on the recent biological studies concerning the ligand C5a and its cellular receptor, the structure/activity relationships so far discerned, signal transduction mechanisms, progress toward identification of receptor antagonists, and some likely directions for future studies. Where appropriate, relevant work on related seven transmembrane segment receptors is discussed.
 ...
PMID:C5A anaphylatoxin and its seven transmembrane-segment receptor. 801 Dec 97

The role of interleukin 6 (IL-6) in the toxic sequelae of sepsis is controversial. To assess the part of IL-6 in inflammatory responses to endotoxin, we investigated eight chimpanzees after either a bolus intravenous injection of Escherichia coli endotoxin (n = 4; 4 ng/kg) or after the same dose of endotoxin with a simultaneous bolus intravenous injection of an anti-IL-6 mAb (30 mg; n = 4). Anti-IL-6 did not affect the induction of the cytokine network (tumor necrosis factor [TNF], soluble TNF receptors types I and II, and IL-8) by endotoxin, nor did it influence the occurrence of a neutrophilic leukocytosis and neutrophil degranulation, as monitored by the measurement of elastase-alpha 1-antitrypsin complexes. In contrast, anti-IL-6 markedly attenuated endotoxin-induced activation of coagulation, monitored with the plasma levels of the prothrombin fragment F1+2 and thrombin-antithrombin III complexes, whereas activation of fibrinolysis, determined with the plasma concentrations of plasmin-alpha 2-antiplasmin complexes, remained unaltered. We conclude that IL-6 does not have a feedback effect on the release of other cytokines after injection of endotoxin, and that it is not involved in endotoxin-induced neutrophilia or neutrophil degranulation. IL-6 is, however, an important intermediate factor in activation of coagulation in low grade endotoxemia in chimpanzees.
 ...
PMID:Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. 814 42

Human blood monocytes adhere rapidly and for prolonged periods to activated platelets that display P-selectin, an adhesion protein that recognizes a specific ligand on leukocytes, P-selectin glycoprotein-1. We previously demonstrated that P-selectin regulates expression and secretion of cytokines by stimulated monocytes when it is presented in a purified, immobilized form or by transfected cells. Here we show that thrombin-activated platelets induce the expression and secretion of monocyte chemotactic protein-1 and IL-8 by monocytes. Enhanced monokine synthesis requires engagement of P-selectin glycoprotein-1 on the leukocyte by P-selectin on the platelet. Secretion of the chemokines is not, however, directly signaled by P-selectin; instead, tethering of the monocytes by P-selectin is required for their activation by RANTES (regulated upon activation normal T cell expressed presumed secreted), a platelet chemokine not previously known to induce immediate-early gene products in monocytes. Adhesion of monocytes to activated platelets results in nuclear translocation of p65 (RelA), a component of the NF-kappaB family of transcription factors that binds kappaB sequences in the regulatory regions of monocyte chemotactic protein-1, IL-8, and other immediate-early genes. However, expression of tissue factor, a coagulation protein that also has a kappaB sequence in the 5' regulatory region of its gene, is not induced in monocytes adherent to activated platelets. Thus, contact of monocytes with activated platelets differentially affects the expression of monocyte products. These experiments suggest that activated platelets regulate chemokine secretion by monocytes in inflammatory lesions in vivo and provide a model for the study of gene regulation in cell-cell interactions.
 ...
PMID:Activated platelets signal chemokine synthesis by human monocytes. 861 86

Acute inflammatory illnesses, including the sepsis syndrome, often include a component of coagulation. A human whole blood culture system was developed so that the relationship between coagulation activation and cytokine responses in the presence or absence of lipopolysaccharide (LPS) could be evaluated. In the absence of LPS stimulation, coagulation activation resulted in a novel pattern of cytokine production. During a 4-hour culture of coagulating blood, significant production of interleukin-8 (IL-8; >2,000 pg/mL) was observed, whereas other proinflammatory cytokines including IL-1 beta, IL-6, or tumor necrosis factor a were undetectable or less than 35 pg/mL. The cytokine profile was distinct from that of fully anticoagulated, LPS-stimulated blood, which showed levels of all the indicated proinflammatory cytokines > or = 2,000 pg/mL over the same time period. Over 24 to 48 hours, the coagulation-induced cytokine response was characterized by marked and sustained IL-8 production, limited IL-6 generation (with kinetics delayed relative to IL-8), and minimal or undetectable tumor necrosis factor alpha levels. The magnitude of the whole blood IL-8 response correlated with the level of coagulation activation as determined by measurement of thrombin-antithrombin III complex formation. The combined stimuli of coagulation activation and LPS challenge induced a synergistic enhancement of IL-8 production but not of IL-6. Coagulation-induced cytokine production and the synergistic production of IL-8 by coagulation and LPS could be attenuated by hirudin or tissue factor pathway inhibitor (TFPI). Studies to elucidate mechanisms implicated (1) the TFPI third Kunitz and carboxy-terminus as important structural components for TFPI regulation of coagulation activation and (2) thrombin as a candidate mediator of the mononuclear cell cytokine response to coagulation activation. In summary, a unique aspect of the crosstalk between the coagulation and cytokine cascades in whole blood is shown with the identification of IL-8 as a key proinflammatory participant.
 ...
PMID:The proinflammatory cytokine response to coagulation and endotoxin in whole blood. 865 18


1 2 3 4 5 6 7 8 9 10 Next >>