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)

Chronic airway inflammation is an important feature of cystic fibrosis (CF), markedly influencing morbidity and mortality. We wanted to assess the contribution of the respiratory epithelium in the mediation of local inflammatory events, and, more particularly, its regulating role through cytokine secretion. We have studied the regulation of interleukin-6 and 8 (IL-6 and IL-8) production by the SV40 transformed airway epithelial cell line JME/CF15 (homozygous for the deletion of Phe 508). We show that unstimulated JME/CF15 cells secrete IL-6 and IL-8. Neutrophil chemotactic activity (NCA) is detected in supernatants. The secretion of IL-6 and IL-8 is increased following stimulation of the JME/CF15 cells by IL-1 beta and neutrophil elastase. Lipopolysaccharide and granulocyte macrophage colony stimulating factor (GM-CSF) have no effect on secretion of IL-6 or IL-8. Neutrophil elastase inactivates recombinant human IL-6 at 37 degrees C in vitro, but has no effect at 4 degrees C, suggesting a proteolytic effect of elastase on IL-6. IL-8 activity remains preserved, even after prolonged exposure to elastase. Our data suggest that the airway epithelium may play an active role in the mediation of neutrophil chemotaxis. Local production of IL-8 in response to elastase and IL-1 beta, together with the inactivation of the anti-inflammatory protein IL-6, may result in a significant upregulation of airway inflammation in cystic fibrosis.
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PMID:Regulation of cytokine secretion by cystic fibrosis airway epithelial cells. 811 34

Incubation of polymorphonuclear leukocytes with chemoattractants, granulocyte-macrophage colony-stimulating factor (GM-CSF), or phorbol 12-myristate 13-acetate (PMA) activated both mitogen-activated protein kinase kinase (MAPKK) and mitogen-activated protein kinase (MAPK). Activation by chemoattractants was rapid and transient, being maximal by 1 min and decreasing by 10 min. The order of efficacy was formyl-met-leu-phe > C5a > > LTB4 > interleukin 8 > platelet-activating factor. In contrast, activation by GM-CSF or PMA was slow and sustained being maximal at 5 min and with little decrease by 30 min. Sustained MAPK activation required continuous activation of the MAPKK. The MAPKK induced by N-formylmethionyl-leucyl-phenylalanine, GM-CSF, or PMA was resolved into two forms by anion exchange chromatography (Mono Q). Both corresponded to a 45-kDa MAPKK antigen by Western blotting and were inactivated by serine/threonine protein phosphatase 2A. Rechromatography of both forms after dephosphorylation resulted in the antigen's eluting slightly earlier on the Mono Q gradient than when in the active state. However, the two peaks remained separate, suggesting that they are not merely different phosphoforms of the same enzyme. The MAPK cascade is a signaling pathway common to many polymorphonuclear leukocyte stimulants, which may be activated transiently or in a sustained manner.
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PMID:Characterization of two different forms of mitogen-activated protein kinase kinase induced in polymorphonuclear leukocytes following stimulation by N-formylmethionyl-leucyl-phenylalanine or granulocyte-macrophage colony-stimulating factor. 814 33

To examine RNA/protein synthesis of neutrophils and related dynamic changes during the inflammatory process, we investigated mRNA expressions in neutrophils, by RNA blot hybridization analyses using 12 different rabbit gene probes. We first selected five candidate genes encoding inflammation-related proteins, i.e. tumor necrosis factor (TNF-alpha) IL-1 alpha, IL-1 beta, neutrophil activating peptide-1/IL-8 (NAP-1/IL-8) and monocyte chemoattractant protein (MCP)-1. We further selected several genes on basis of the results from gene subtraction between cDNA libraries from neutrophils at an early (5 h) and at a late (24 h) stage of casein-induced acute peritonitis in rabbits, i.e. immune activation gene-2 (Act-2), migration inhibitory factor-related protein-8 (MRP-8), MRP-14, gamma-actin, and formyl-methionyl-leucyl-phenylalanine receptor (fMLP-R), and ferritin light (L) chain. In addition to these genes we used ferritin heavy (H) chain gene, another component of the ferritin molecule. We examined mRNA expressions by cytoplasmic slot blot analysis of the above 12 genes in neutrophils obtained from blood and from various stages of casein-induced inflammation in rabbits. The observed patterns of mRNA expression kinetics were classified into three. Pattern 1: mRNAs of MRP-8, MRP-14, and gamma-actin were constitutively expressed in blood neutrophils, and increased rapidly after emigration into inflammatory sites. Pattern 2: mRNAs of IL-1 beta, NAP-1/IL-8, Act-2, and fMLP-R were undetectable in blood neutrophils, and were induced rapidly after the onset of inflammation. Pattern 3 mRNAs of ferritin L and H chain were induced slowly, and increased with progression of the inflammatory process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dynamic changes in mRNA expression of neutrophils during the course of acute inflammation in rabbits. 814 23

Cytokines such as tumor necrosis factor alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 8 (IL-8), IL-6, IL-1 alpha, and IL-1 beta produced during the immune and inflammatory responses to bacterial stimuli have been reported to interact with polymorphonuclear neutrophil (PMN) activities. However, contradictory findings on their direct and priming effects on the PMN oxidative burst, which is essential for bacterial killing, have been reported. We have used a flow cytometry method to study the effects of these cytokines on the oxidative burst of PMN in whole blood to avoid PMN activation related to isolation procedures. None of the cytokines tested directly activated the PMN oxidative burst, but they did have differential priming effects on the oxidative burst in response to bacterial N-formyl peptides. TNF, GM-CSF, and IL-8 strongly primed a subpopulation of PMN to produce H2O2 in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP), while IL-1 alpha, IL-1 beta, and IL-6 failed to do so. Furthermore, the addition of TNF, GM-CSF, or IL-8 to whole blood increased the capacity of a subpopulation of PMN to bind N-formyl peptides, a phenomenon that could account, at least in part, for the strong H2O2 production in response to FMLP after priming by the cytokines. The size of the primed hyperresponsive subpopulation was greater after priming with TNF or GM-CSF than after priming with IL-8. However, GM-CSF, TNF, and IL-8 at suboptimal concentrations cooperated in the induction of a subpopulation hyperresponsive to FMLP. These results show that, of the various proinflammatory cytokines tested, TNF, GM-CSF, and IL-8 strongly prime the PMN oxidative burst in response to bacterial peptides in whole blood and suggest that these cytokines may play a critical role in bacterial killing in vivo.
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PMID:Differential priming effects of proinflammatory cytokines on human neutrophil oxidative burst in response to bacterial N-formyl peptides. 818 40

Neutral endopeptidase 24.11 (NEP/CALLA/CD10), an enzyme expressed on early lymphoid progenitors, neutrophils, and various other cell types, inactivates many biologically active peptides, including the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Inhibition of CD10/NEP on the surface of human neutrophils (PMNs) in vitro inhibits migration toward this chemotaxin, suggesting that enzymatic inactivation by NEP regulates the neutrophil response to fMLP. Because PMNs in inflammatory sites are exposed to various cytokines, we evaluated the effects of selected cytokines on CD10/NEP activity in vitro. Of five cytokines tested--interleukin-1 (IL-1), IL-6, and IL-8, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor (GM-CSF)--GM-CSF provided the most consistent increase in surface NEP activity. Low concentrations (10(-9)-10(-7) M) of GM-CSF increased NEP activity in a time- and concentration-dependent manner to more than 225% that of control (phosphate-buffered saline-treated) cells. Cytofluorometry of cells stained with a fluorescent antibody to CD10 indicated that GM-CSF increased expression of surface CD10/NEP antigen in a similar manner. The effect of GM-CSF on NEP activity was enhanced still further by simultaneous exposure to IL-1, suggesting that combinations of cytokines may direct and regulate the neutrophil response within an inflammatory site. Rapid upregulation of CD10/NEP underscores the importance of this enzyme for control of peptide mediators of inflammation.
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PMID:Up-regulation of neutral endopeptidase (CALLA) in human neutrophils by granulocyte-macrophage colony-stimulating factor. 831 51

Lung giant cell carcinoma-derived chemotactic protein (LUCT)/IL-8 and fMet-Leu-Phe stimulate phosphorylation of a 64-kd protein (p64) in 32P-labeled human polymorphonuclear leukocytes (PMNs). The p64 was purified from cytosol of human PMNs (1.8 x 10(9) cells) by DEAE-Sepharose CL6B column chromatography, hydroxyapatite HPLC, and reverse-phase HPLC. By hydroxyapatite HPLC, p64s were separated and produced two peaks containing both nonphosphorylated and phosphorylated p64. Amino acid composition of each p64 was determined. Each p64 was directly subjected to amino acid sequencing, but the amino acid residue in the amino-terminal of the proteins could not be detected. From the results of amino acid composition and other characters of p64, it is suggested that p64 is identical to l-plastin, which is a leukocyte-specific protein.
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PMID:Characterization of a 64-kd protein phosphorylated during chemotactic activation with IL-8 and fMLP of human polymorphonuclear leukocytes. II. Purification and amino acid analysis of phosphorylated 64-kd protein. 833 74

We looked for chemotaxin/interleukin 8 (CT/IL-8) activity in the culture fluids of 97 human leukemia cell lines and found it in two of the T cell lines, six of the myeloid cell lines, and one of the normal B-cell lines. It was particularly strong in the culture fluids of two cell lines. These cell lines secreted a chemotactic protein into the culture fluids under certain conditions of stimulation with phorbol-12-myristate 13-acetate (PMA), lipopolysaccharide, or hemagglutinin-P. A myeloid leukemia cell line, ML-1, secreted an inducible chemotaxin when stimulated with PMA (1 ng/ml) for 24 h. We purified the chemotaxin from ML-1 cell culture fluid using an improved procedure: concentration with DEAE-Sepharose CL-6B and CM-Sepharose CL-6B, CM-Sepharose column chromatography, and reverse-phase 5TMS-300 column on HPLC with the retention time coinciding with that of LUCT/IL-8 [Suzuki et al., 1989, J. Exp. Med. 169, 1895]. The yield was 200 micrograms protein from 6 liters of the culture fluid. The N terminus of CT/IL-8 was AVLPR-SAKELRXQXIKTYSK- - -, the same as that of LUCT/IL-8, which is constitutively secreted from lung giant cell carcinoma LU65C cells. The optimal concentration in the chemotactic activity of CT/IL-8, equivalent to that of bacterial chemotactic peptide fMet-Leu-Phe (10 nM), was found to be 5 nM. The results show that this chemotaxin is identical to LUCT/IL-8.
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PMID:Isolation and amino acid sequence of a chemotactic protein, LECT/interleukin 8, from a human myeloid leukemia cell line, ML-1. 834 17

The interaction of interleukin 8 (IL-8) with heparin was studied by using synthetic IL-8 analogs with C- and N-terminal truncations. Elimination of the N-terminal region preceding the first cysteine, which constitutes the IL-8 receptor binding site, did not affect the affinity to heparin-Sepharose. Affinity, however, decreased with progressive truncation at the C terminus, and no binding was observed when the C-terminal alpha-helix was eliminated. The effect of heparin and other glycosaminoglycans on IL-8 activity was also tested. When IL-8 was applied together with heparan sulfate, neutrophil chemotaxis in vitro was enhanced up to 4-fold, and the stimulus-dependent increase in cytosolic free Ca2+ increased markedly in both rate and peak value. Heparin had a similar effect on the Ca2+ response but did not enhance chemotaxis. The glycosaminoglycans by themselves did not elicit neutrophil responses. Their enhancing effect was restricted to stimulation with IL-8 and was not observed when the unrelated chemoattractant fMet-Ile-Phe-Leu was used as the stimulus. Elastase released from stimulated neutrophils was inhibited by heparin, heparan sulfate, and, to a lesser extent, chondroitin sulfate B, confirming previous observations. Taken together, these results suggest that heparan sulfate, which is present on the endothelial cell surface and in the basement membrane, may have a dual function in diapedesis, promotion of IL-8-dependent transmigration of neutrophils, and protection of the tissue microenvironment from damage by lytic enzymes released from the migrating cells.
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PMID:Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. 834 30

We investigated the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the 5-lipoxygenase (5-LO) component of the leukotriene (LT) biosynthetic pathway of human neutrophils, in order to better understand the mechanism whereby the cytokine primes for LT synthesis. We found that GM-CSF increased 5-LO activation elicited by platelet-activating factor (PAF), N-formyl-methionyl-leucyl-phenylalanine (fMLP), C5a, LTB4, IL-8 and calcium ionophore A23187, as determined by using an exogenous substrate. A close correlation was observed between the priming kinetics of GM-CSF on 5-LO activation and on LT synthesis; moreover, the effects of the cytokine on both 5-LO activation and LT synthesis were inhibited when the cells had been exposed to either the protein synthesis inhibitor, cycloheximide (CX), or the transcription inhibitor, actinomycin D (AD), prior to incubation with GM-CSF. These results raise the possibility that the priming by GM-CSF of LT synthesis may involve an effect of the cytokine on 5-LO protein synthesis and gene expression.
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PMID:Enhancement by GM-CSF of agonist-induced 5-lipoxygenase activation in human neutrophils involves protein synthesis and gene transcription. 835 16

Interleukin-8 (IL-8) such as LUCT (lung giant cell carcinoma-derived chemotactic protein), NAP (neutrophil activating protein) and MDNCF (monocyte-derived neutrophil chemotactic factor), and formylmethionyl-leucyl-phenylalanine (fMLP) are well-known chemoattractants for human polymorphonuclear leukocytes (PMNs) and are able to stimulate phosphorylation of 64-kd protein (p64) in these leukocytes. To elucidate the molecular mechanism of PMN activation with chemoattractants, we investigated the phosphorylation process of p64 in an intact cell. 32P-Labeled PMNs were stimulated with LUCT/IL-8, fMLP, leukotriene B4, or C5a, and phosphorylated proteins were analyzed by two-dimensional electrophoresis and autoradiography. A marked phosphorylation of p64 was observed after stimulation. A new spot of phosphorylated p64 (pp64) could be detected on the gel stained with Coomassie Brilliant Blue, indicating that the isoelectric point (pI) of p64 shifted from 5.3 to a more acidic pI by the phosphorylation forming pp64. The spot of pp64 was shown to be dephosphorylated to p64 by treatment with calf intestine alkaline phosphatase. Other proteins having molecular masses 82, 66, 58, 55 and 50 kd were also phosphorylated. The fMLP-stimulated phosphorylation was time-dependent and saturated within 5 min. Maximum stimulation was achieved with 10 nM fMLP. Phosphoamino acid analysis revealed phosphorylation of serine residues in pp64. Staurosporine (100 nM) and W-7 (100 microM) significantly inhibited the phosphorylation of p64, but H-7 slightly inhibited it. H-8 and herbimycin A did not effect phosphorylation. Phorbol myristate acetate was found to stimulate significantly. Protein kinase C did not stimulate the phosphorylation. These data suggest that protein kinase C and calmodulin-like protein are indirectly involved in the phosphorylation of p64 during chemoattractant-activation of PMN.
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PMID:Characterization of a 64-kd protein phosphorylated during chemotactic activation with IL-8 and fMLP of human polymorphonuclear leukocytes. I. Phosphorylation of a 64-kd protein and other proteins. 839 62


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