UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of the respiratory burst of neutrophil leukocytes with chemotactic agonists requires two concomitant signal transduction pathways. One is calcium dependent and leads to activation of phospholipase C, the other is calcium independent but sensitive to the fungal metabolite wortmannin, a specific inhibitor of phosphatidylinositide 3-kinase (PI 3-kinase). Two isoforms of PI 3-kinase have been characterized in neutrophils, the p85/p110 PI 3-kinase alpha and the p101/p120 PI 3-kinase gamma. The relative contribution of the two PI 3-kinases in mediating chemoattractant-stimulated superoxide production and exocytosis in neutrophils in unclear. Here, we report that the protein tyrosine kinase inhibitor genistein markedly attenuates chemoattractant-stimulated phosphatidylinositol (3,4,5)-trisphosphate (PIP3) formation in neutrophils. PI 3-kinase activity in untreated cells is bimodal showing a maximum production after 10-15 sec that protracts with a lower PIP3 formation for approximately 2 min and returns to basal levels after 2-3 min. Genistein at 100 microM strongly inhibits PIP3 elevation and the fMet-Leu-Phe-stimulated respiratory burst. The activity of purified PI 3-kinase, however, is not altered in the presence of genistein, suggesting that the genistein-sensitive intermediate is located between the G-protein-coupled receptor and PI 3-kinase. Expression of a dominant negative form of PI 3-kinase alpha in GM-1/CXCR1 cells, a promyelolocytic cell line transfected with the G-protein-coupled receptors CXCR1, considerably reduces IL-8-stimulated PIP3 formation. The present observations suggest that in phagocytes stimulated with agonists of G-protein-coupled receptors the bulk of PIP3 is generated by PI 3-kinase alpha, which is activated through a genistein-sensitive target, presumably a protein tyrosine kinase.
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PMID:G-protein coupled receptor-mediated activation of PI 3-kinase in neutrophils. 970 65

The aims of this study were to examine the plasma availability of tryptophan, the precursor of 5-hydroxytryptamine (5-HT), and serum cytokines, such as interleukin-6 (IL-6) and IL-8, in normal elderly volunteers and in patients with Alzheimer's disease (DAT). Elderly normal volunteers (mean age = 78.3 +/- 5.7 years) had a significantly lower tryptophan/competing amino acids (valine + leucine + isoleucine + phenylalanine + tyrosine) ratio than younger subjects (mean age = 32.9 +/- 8.1 years). In normal volunteers, there were significant and inverse relationships between age and either plasma tryptophan or the tryptophan/competing amino acids ratio, and between the availability of tryptophan to the brain and serum IL-6 or IL-8. DAT patients had significantly higher serum IL-6, but not IL-8, than age-matched normal volunteers. There were no significant differences in the availability of tryptophan to the brain between DAT patients and age-matched normal volunteers. The results suggest that: 1) in normal humans, the availability of plasma tryptophan to the brain decreases with age, and with activation of the immune system; and 2) increased production of IL-6 may play a role in the pathogenesis of DAT.
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PMID:Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer's disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT. 982 23

5-Hydroxy- and 5-oxo-eicosatetraenoate (5-HETE and 5-oxoETE) activate polymorphonuclear neutrophils (PMNs) through a common, receptor-like recognition system. To define this system, we examined the interaction of these eicosanoids with human PMNs. PMNs esterified 5-[3H]HETE to glycerolipids at 37 and 4 degreesC. At 37 but not 4 degreesC, the cells also hydroxylated the label to 5, 20-[3H]diHETE. The acyl:CoA synthetase blocker, triacsin C, inhibited esterification but also led to an increase in the hydroxylation of the label. PMNs processed 5-[3H]oxoETE through the same pathways but only or principally after reducing it to 5-[3H]HETE (37 or 4 degreesC). In the presence of these varying metabolic reactions, PMNs (37 or 4 degreesC; +/- triacsin C) could not be shown to receptor bind either radiolabel. Plasma membranes isolated from PMNs esterified but unlike whole cells did not reduce or hydroxylate 5-[3H]oxoETE. Triacsin C blocked esterification, thereby rendering the membranes unable to metabolize this radiolabel. Indeed, triacsin C-treated membranes bound (Kd = 3.8 nM) 5-[3H]oxoETE specifically and reversibly to 86 pmol of sites per 25 micrograms of membrane protein. 5-OxoETE, 5-HETE, and 5,15-diHETE displaced this binding at concentrations correlating with their potency in eliciting PMN Ca2+ transients. GTP and GTPgammaS, but not ATP or ATPgammaS, also reduced 5-[3H]oxoETE binding, whereas 15-HETE, leukotriene B4, platelet-activating factor, IL-8, C5a, and N-formyl-Met-Leu-Phe lacked this effect. We conclude that PMNs and their plasma membranes use an acyl:CoA synthetase-dependent route to esterify 5-HETE and 5-oxoETE into lipids. Blockade of the synthetase uncovers cryptic plasmalemma sites that bind 5-oxoETE with exquisite specificity. These sites apparently mediate responses to the 5-oxo class of eicosanoids and are likely members of the serpentine superfamily of G protein-linked receptors.
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PMID:Receptors for the 5-oxo class of eicosanoids in neutrophils. 982 88

Neutrophils recovered from inflammatory exudates possess increased levels of IL-8, but exposure of neutrophils to chemoattractants results in only a modest stimulation of IL-8 generation. This study was undertaken to explore the hypothesis that IL-8 generation in these cells is dependent upon the process of migration. Neutrophils synthesized up to 30 times as much IL-8 during migration in response to a gradient of diverse chemoattractants than they did when stimulated directly by the attractants in the absence of a gradient. This IL-8 response was dependent on migration since it was not observed in cells exposed to concentration gradients of chemoattractants under conditions that prevented cell movement. While actinomycin-D (1 microg/ml) had little influence on the generation of IL-8 during chemotaxis, the protein synthesis inhibitor cycloheximide (10 microg/ml) markedly blunted the accumulation of cell-associated IL-8, suggesting that new protein synthesis from preexisting mRNA was responsible for the effect. Consistent with this interpretation, migrating cells incorporated over 10 times as much [3H]leucine into IL-8 as did nonmotile neutrophils exposed to chemoattractants. A substantial portion of the IL-8 generated during chemotaxis was released upon subsequent metabolic stimulation. Thus, the IL-8 synthesized during chemotaxis is uniquely positioned to exert a regulatory influence on inflammatory processes governed by neutrophilic leukocytes responding to inflammatory and infectious stimuli.
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PMID:Chemotactic migration triggers IL-8 generation in neutrophilic leukocytes. 991 36

All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.
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PMID:CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes. 1035

Interleukin-8 is a cytokine produced by mononuclear cells that is involved in polymorphonuclear neutrophil leukocyte (PMN) recruitment and activation. Several studies have previously demonstrated a leukocyte activation during hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been found to play a role in the prevention of atherothrombotic disease. The purpose of this study was to determine interleukin-8 (IL-8) mRNA expression and ex vivo production from peripheral blood mononuclear cells (PBMCs) and IL-8-dependent PMN activation of hypercholesterolemic (HC) patients with respect to normocholesterolemic (NC) subjects. Using Northern blot analysis, we found a four- and threefold increase in the amount of IL-8 transcript in PBMC from HC patients, in unstimulated and LPS stimulated cultures, respectively. A specific immunoassay showed a correspondingly significant increase of IL-8 immunoactivity in the conditioned medium of PBMC from HC subjects as compared with controls (unstimulated PBMC: 15 +/- 4 vs. 4.2 +/- 3 ng/ml; P < 0.0001; LPS stimulated PBMC: 65.3 +/- 8 vs. 36.6 +/- 9 ng/ml; P < 0.0001). PMN of HC patients stimulated with IL-8 showed a reduced elastase release with respect to NC subjects before physiological granule release after f-Met-Leu-Phe (fMLP) treatment. These results indicate an upregulation of the IL-8 system in dyslipidemic patients and provide evidence for ongoing in vivo IL-8-dependent PMN activation during hypercholesterolemia.
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PMID:Peripheral blood mononuclear cell production of interleukin-8 and IL-8-dependent neutrophil function in hypercholesterolemic patients. 1091 72

We have reported that endothelial interleukin 8 (IL-8) induces apoptosis in leukemic cells in vitro and in vivo, and that interaction between endothelial cells and leukemic cells causes induction of apoptosis through the release of endothelial IL-8 (Y. Terui et al., Biochem. Biophys. Res. Commun., 243: 407-411, 1998; Y. Terui et al., Blood, 92: 2672-2680, 1998). Here, we examined whether a pentapeptide corresponding to the NH2-terminal region of endothelial IL-8 can induce apoptosis in leukemic cells. The NH2-terminal pentapeptide Ala-Val-Leu-Pro-Arg (AVLPR) was found to significantly induce apoptosis in the leukemic cell lines K562, HL-60, Jurkat, and Daudi, as compared with the COOH-terminal pentapeptide Arg-Glu-Ala-Asn-Ser (REANS). Moreover, the NH2-terminal pentapeptide AVLPR significantly inhibited growth of i.p. and s.c. tumor masses of K562 cells and induced apoptosis in these cells in vivo. The active site of endothelial IL-8 is the NH2-terminal pentapeptide AVLPR, and this may serve as a new therapy for hematological malignancies.
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PMID:NH2-terminal pentapeptide of endothelial interleukin 8 is responsible for the induction of apoptosis in leukemic cells and has an antitumor effect in vivo. 1058 77

Inositol hexaphosphate (IP6) has anti-cancer properties, but recently other extracellular functions have been observed for IP6, including enhancing superoxide production and phagocytosis by neutrophils in the presence of microbial stimuli. This study investigated other inflammatory functions of IP6 on adherent neutrophils. The effect of IP6 on the release of IL-8, tumour necrosis factor (TNF-alpha) and IL-6 by neutrophils attached to either plastic or laminin for up to 6 hours in response to stimulation with lipopolysaccharide or N-formyl-Met-Leu-Phe (fMLP) was investigated. An increase in IL-8 secretion by stimulated cells occurred in the presence of IP6. The incubation of cells attached to laminin with IP6 alone (100-250 BM) did not effect cell morphology, but in the presence of 10(-7) M fMLP altered cell shape. A direct effect of IP6 on cell function was to trigger a sustained assembly of F-actin. Thus, exposure of neutrophils to low levels of IP6 appears to modulate selective neutrophil functions.
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PMID:Effect of IP6 on human neutrophil cytokine production and cell morphology. 1062 45

Interferon-gamma-inducible 10 kd protein (IP-10) is an ELR (Glu-Leu-Arg)(-) alpha chemokine with known chemotactic effects on T cells and monocytes, as well as anti-viral, anti-angiogenic, and anti-tumor effects. Previous studies have demonstrated that in cultured rat astrocytes and microglia, stimulation with LPS or virus can induce the expression of IP-10. In this study, we determined the pattern of IP-10 gene induction in primary human microglia and astrocytes by cytokines and LPS using ribonuclease protection assay. The expression of IP-10 mRNA was compared with that of other alpha (IL-8) and beta chemokines. The results showed that in human microglia, IP-10 expression was induced equally potently by LPS, IFNbeta or IFNgamma. "Proinflammatory" cytokines IL-1beta or TNFalpha also induced small amounts of IP-10 mRNA. "Anti-inflammatory" cytokines IL-4, IL-10 and TGFbeta were ineffective in inducing IP-10 in microglia. In human astrocytes, induction of IP-10 mRNA by cytokines was similar to that in microglia. LPS, however, was ineffective in inducing IP-10 in human astrocytes. The monocyte chemoattractant beta-chemokine I-309 mRNA was induced in human astrocytes and microglia by IFNbeta or IFNgamma, or by LPS in microglia, showing a tight co-regulation with IP-10 mRNA expression. In contrast to the potent induction of IP-10 and I-309 by IFNs in human glia, the ELR(+) alpha chemokine IL-8 mRNA was induced by IL-1beta and TNFalpha, and to a lesser extent by IFNbeta in microglia. IFNbeta but not IFNgamma was effective in inducing the expression of beta chemokines MIP-1alpha and MIP-1beta in human microglia, with the levels of mRNA similar to those induced by IL-1beta or TNFalpha. Neither MIP-1alpha nor MIP-1beta mRNAs were induced by any stimulation in human astrocytes. The induction of RANTES mRNA in microglia by IFNbeta, IL-1beta or TNFalpha was variable, showing no to low level expression depending on the case, whereas LPS provided a consistent inducing signal. In astrocytes, only cytokine combinations (IFN + IL-1beta) effectively induced the RANTES mRNA. These results demonstrate that distinct sets of chemokine genes are induced in human glial cells by cytokines and interferons. These results may have wide implications for inflammatory, vascular and neoplastic diseases of the CNS.
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PMID:Distinct patterns of stimulus-inducible chemokine mRNA accumulation in human fetal astrocytes and microglia. 1069 46

IL-8 and related Glu-Leu-Arg (ELR+) CXC chemokines are potent chemoattractants for neutrophils but not for monocytes. IL-13 and IL-4 strongly increased CXCR1 and CXCR2 chemokine receptor expression in human monocytes, macrophages, and dendritic cells. The effect was receptor- and cell type-selective, in that CCRs were not increased and no augmentation was seen in neutrophils. The effect was rapid, starting at 4 h, and concentration dependent (EC50 = 6.2 and 8.3 ng/ml for CXCR1 and CXCR2, respectively) and caused by new transcriptional activity. IL-13/IL-4-treated monocytes showed increased CXCR1 and CXCR2 membrane expression. IL-8 and related ELR+ chemokines were potent and effective chemotactic agents for IL-13/IL-4-treated monocytes, but not for untreated mononuclear phagocytes, with activity comparable to that of reference monocyte attractants, such as MCP-1. In the same cells, IL-8 also caused superoxide release. Macrophages and dendritic cells present in biopsies from Omenn's syndrome and atopic dermatitis patients, two Th2 skewed pathologies, expressed IL-8 receptors by immunohistochemistry. These results show that IL-13 and IL-4 convert IL-8 and related ELR+ chemokines, prototypic neutrophil attractants, into monocyte chemotactic agonists, by up-regulating receptor expression. Therefore, IL-8 and related chemokines may contribute to the accumulation and positioning of mononuclear phagocytes in Th2-dominated responses.
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PMID:Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. 1072 48

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