UNIPROT:P10145 - FACTA Search

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)

Interleukin-8 (IL-8), growth-related oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2 (NAP-2), epithelial cell-derived neutrophil activating peptide- 78 (ENA-78), and granulocyte chemoattractant protein-2 are potent neutrophil chemoattractants 40-90% identical in amino acid sequence that comprise a subgroup of human CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR). Two human chemotactic receptor subtypes for IL-8, named IL-8 receptors (IL8R) A and B, have been cloned. They are 78% identical in amino acid sequence, coexpressed in neutrophils, and distinguished by their different selectivities for GROalpha and NAP-2. Their selectivity for other ELR+ CXC chemokines has not been previously reported. By measuring calcium flux in human embryonic kidney 293 cells transfected with plasmids encoding IL8RA or IL8RB, we have now defined receptor selectivity for GRObeta, GROgamma, and ENA-78. The rank order of agonist potency, based on inspection of the mean effective concentration values (EC50), for IL8RB was GROgamma (1 nM) > IL-8 (4 nM) approximately GROalpha (5 nM) approximately GRObeta (4 nM) approximately NAP-2 (7 nM) > ENA-78 (11 nM), and for IL8RA was IL-8 (4 nM) >>> ENA-78 (40 nM) approximately NAP-2 (45 nM) > GROalpha (63 nM) approximately GROgamma (65 nM) >> GRObeta. The maximal response of IL8RA to IL-8 was at least 2-fold greater than the other five chemokines. All six agonists for IL8RB competed for high affinity 125I-IL-8, -GROalpha, -NAP-2, and -ENA-78 binding sites at IL8RB. GROalpha, GRObeta, GROgamma, NAP-2, and ENA-78 competed weakly for the high affinity IL-8 binding site at IL8RA. Thus, IL8RA and IL8RB are both highly selective for IL-8 and have similar sequences but differ dramatically in their selectivity for all other ELR+ CXC chemokines tested. These findings have important implications for developing novel neutrophil-specific anti-inflammatory drugs directed against the CXC chemokine signaling system.
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PMID:The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor. 870 98

CXCR2 is a seven-transmembrane receptor that transduces intracellular signals in response to the chemokines IL-8, MGSA/GRO, and other ELR motif-containing CXC chemokines by coupling to heterotrimeric GTP-binding proteins. In this study, we have mutated two putative G protein-coupling regions of CXCR2 and characterized the effects of these mutations on ligand-activated signal transductions: aspartic acid 89 in the second transmembrane domain and the HRAMR sequence (BBXXB motif, found in the third intracellular loop where B indicates a basic amino acid and X represents any amino acid). The Asp89 was replaced by either asparagine (D89N) or glutamic acid (D89E). For the BBXXB motif, the first two basic amino acids were mutated to two neutral isoleucines (HR-II), or alternatively, two isoleucines were inserted between alanine and methionine (II-insert). When expressed in human embryonic kidney 293 cells, the D89E mutant was localized intracellularly with no detectable cell surface expression. In contrast, D89N, HR-II, and II-insert mutants displayed cell surface expression, with Kd values and expression levels similar to that of the wild-type transfectant. The ability of the mutants to transduce signal was assessed by ligand-stimulated GTPgamma35S binding, mobilization of intracellular free Ca2+, and chemotaxis assays. Both D89N and HR-II mutants signaled similarly to a wild-type receptor in all three assays. However, the II-insert mutant exhibited a loss of ligand-stimulated GTPgamma35S binding, calcium mobilization, and chemotaxis. Unexpectedly, this receptor underwent ligand-induced sequestration comparable to wild-type CXCR2. These data indicate that Asp89 and the basic amino acids in the third intracellular domain do not play essential roles in ligand-induced signal transduction through CXCR2. However, proper secondary structure and orientation of the third intracellular loop of CXCR2 are essential for ligand-mediated signal transduction but not for receptor sequestration.
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PMID:Interruption of G protein-coupling in CXCR2 does not alter ligand binding, but eliminates ligand-activation of GTPgamma35S binding, calcium mobilization, and chemotaxis. 939 46

Synthetic fluorogenic substrates, like the CellProbe reagents, can determine enzymes in vital human spermatozoa. These substrates will enter the cells without previous cell permeabilization and exhibit fluorescence after cleavage depending on enzyme activity. They consist of different peptide sequences, specific for the enzymes, and a fluorescein- or rhodamine 110-dye moiety. The number of positive cells and the intensity of the fluorescence can be determined by flow cytometric analysis. We investigated several enzymes (peptidases, proteinases, esterases, elastases and collagenases) in intact spermatozoa before and after cryoprotection. Semen samples with normal spermiogram parameters were cryoprotected using the freezing medium TEST yolk buffer (TYB). Fresh spermatozoa showed a marked fluorescence after incubation with the synthetic substrates for the aminopeptidase M, butyryl esterase, fluorescein diacetate (FDA)-and FDA/sodium fluoride (NAF)-esterase, ala-ala-pro-val (AAPV)-elastase, gly pro-leu-gly pro-(GPLGP)-collagenase, gly gly leu-(GGL)-subtilisin as well as lys-ala-(LA)-dipeptidyl peptidase (DPP) II. After cryopreservation the spermatozoal fluorescence increased applying substrates for butyryl esterase (P<0.05), prolyl-aminopeptidase (P<0.001) and val-lys-(VK)-cathepsin (P<0.001) most probably due to elevated enzyme activities. The activities of FDA-esterase (P<0.05) and FDA/NAF-esterase (P<0.05), AAPV-elastase (P<0.01), GPLGP-collagenase (P<0.05) and GGL-subtilisin (P<0.001) decreased after cryopreservation. The substrates for arg-gly glut-ser-(RGES)-elastase, gly phenyl-gly ala-(GFGA)-collagenase and threo-pro-(TP)-cathepsin were not cleaved before as well as after cryostorage. The substrates for subtilisin an
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PMID:Flow cytometric analysis of enzymes in live spermatozoa before and after cryostorage. 1113 45

The aim of this study was to develop new biocompatible coatings for bone implants by the alternating deposition of oppositely charged polyelectrolytes. Polyelectrolyte films were built up with different terminating layers on which SaOS-2 osteoblast-like cells and human periodontal ligament (PDL) cells were grown. The terminating layer was made of one of the following polyelectrolytes: poly(ethylene imine) (PEI), poly(sodium 4-styrenesulfonate) (PSS), poly(allylamine hydrochloride) (PAH), poly(L-glutamic acid) (PGA), or poly(L-lysine) (PLL). Cell adherence, viability, stability of osteoblast phenotype, and inflammatory response were studied. Adherence and viability were good on all terminating layers except the PEI-terminating layer, which was cytotoxic. Maintenance of osteoblast phenotype marker expression was observed on PSS- and PGA-terminating films for both cell types, whereas downregulation, associated with the induction of Interleukin-8 (IL-8) secretion, was detected on PEI and PAH for both cell types and on PLL for PDL cells. These results suggested a good biocompatibility of PSS- and PGA-ending films for PDL cells and of PSS-, PGA-, and PLL-terminating films for SaOS-2 cells. As a result, polyelectrolyte multilayer films could emerge as new alternatives for implant coatings.
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PMID:Viability, adhesion, and bone phenotype of osteoblast-like cells on polyelectrolyte multilayer films. 1194 25

Chemotaxis of blood monocytes into the vessel wall together with the change of the relative content of the extracellular matrix (ECM) proteins at sites of predilection is an early cellular marker of atherogenesis. To examine the influence of ECM proteins on secretion of chemoattractants by endothelial cells (EC), porcine EC were seeded on gelatin (G), fibronectin (Fn) and fibrinogen (Fg). After 24 h cells seeded on G and Fn showed the histiotypic 'cobblestone'-morphology whereas cells seeded on Fg did not. Chemotactic activity for monocytes in supernatants from cells seeded on Fg was more than two-fold higher compared with G and was independent of soluble Fn or Fg in the supernatant. Quantification of monocyte chemoattracting protein-1, PDGF-AB and IL-8 in EC supernatants showed that Fg led to a significant increase in secretion of all three proteins compared with cells cultured on G. Preincubation of porcine EC with the tripeptide arginine-glycine-aspartic acid, as inhibitor of binding of Fg to integrin receptors, but not with the control tripeptide arginine-glycine-glutamic acid showed a decrease in chemotactic activity for cells cultured on Fg but not on Fn or G. Inhibition of protein kinase C (PKC) activity in EC by GF109203 resulted in a decrease of fibrinogen-induced chemotactic activity. Also the tyrosine-kinase inhibitor herbimycin inhibited fibrinogen mediated secretion of chemokines. The role of the PKC pathway for matrix mediated signal transduction is further corroborated by Fg-dependent induction of the PKC isoform delta. These data indicate an integrin-dependent signal transduction pathway leading to induction of chemotactic activity by the ECM protein fibrinogen. This mechanism may contribute to induction of chemokines in early atherosclerotic lesions.
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PMID:Fibrinogen induces chemotactic activity in endothelial cells. 1235 70

Increasing evidence suggests that the chemokine interleukin (IL)-8/CXCL8 plays important roles in CNS development, neuronal survival, modulation of excitability, and neuroimmune response. Recently, we have shown that CXCL8 can acutely modulate ion channel activity in septal neurons expressing receptors CXCR1 and/or CXCR2. This was a surprising finding, insofar as CXCR1 expression had not been described for the mammalian brain. Here we investigated whether CXCR1 transcripts are present in other brain regions, whether they are expressed at the single-cell level in molecularly identified neurons and astrocytes, and how they are regulated during early postnatal development. In addition, possible cellular colocalization of CXCR1 and CXCR2 transcripts was examined. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed that CXCR1 mRNAs were expressed in the septum, striatum, hippocampus, cerebellum, and cortex (temporoparietal and entorhinal) at different levels and appeared to be regulated independently from CXCR2 during development. By using RT multiplex PCR on acutely dissociated cells from these brain regions, we show that CXCR1 transcripts were expressed in 83% of 84 sampled neurons displaying cholinergic (choline acetyltransferase mRNAs), gamma-aminobutyric acidergic (glutamic acid decarboxylases 65 and 67 mRNAs), or glutamatergic (vesicular glutamate transporters 1 and 2 mRNAs) phenotypes. CXCR1 and CXCR2 transcripts were colocalized in 45% of neurons sampled and also were present in some glial fibrillary acidic protein mRNA-expressing astrocytes. This is the first study to demonstrate the widespread expression of CXCR1 transcripts in the brain and suggests that CXCR1 may have hitherto unsuspected roles in neuromodulation and inflammation.
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PMID:Widely expressed transcripts for chemokine receptor CXCR1 in identified glutamatergic, gamma-aminobutyric acidergic, and cholinergic neurons and astrocytes of the rat brain: a single-cell reverse transcription-multiplex polymerase chain reaction study. 1451 58

CXC chemokines bearing the glutamic acid-leucine-arginine (ELR) motif are crucial mediators in neutrophil-dependent acute inflammation. Interestingly, however, Interleukin (IL)-8/CXC ligand (CXCL) 8 is expressed in human milk in biologically significant concentrations, and may play a local maturational role in the developing human intestine. In this chemokine subfamily, there are six other known peptides beside IL-8/CXCL8, all sharing similar effects on neutrophil chemotaxis and angiogenesis. In this study, we measured the concentrations of these chemokines in human milk, sought their presence in human mammary tissue by immunohistochemistry, and confirmed chemokine expression in cultured human mammary epithelial cells (HMECs). Each of the seven ELR(+) CXC chemokines was measurable in milk, and except for NAP-2/CXCL7, these concentrations were higher than serum. The concentrations were higher in colostrum (except for GRO-beta/CXCL2 and NAP-2/CXCL7), and correlated negatively with time elapsed postpartum. IL-8/CXCL8, GRO-gamma/CXCL3, and ENA-78/CXCL5 concentrations were higher in preterm milk. There was intense immunoreactivity in mammary epithelial cells for all ELR(+) CXC chemokines, and the intensity of staining was higher in breast tissue with lactational changes. The supernatants from confluent HMEC cultures also contained measurable concentrations of all the seven ELR(+) CXC chemokines. These results confirm that all ELR(+) CXC chemokines are actively secreted by the mammary epithelial cells into human milk. Further studies are needed to determine if these chemokines share with IL-8/CXCL8 the protective effects on intestinal epithelial cells.
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PMID:ELR+ CXC chemokines in human milk. 1458 Oct 3

The effects of cryopreservation on two characteristics of human spermatozoa were investigated: the early phases of disturbed plasma membrane function and the activity of enzymes in intact spermatozoa. The membrane function was detected by means of the calcium-dependent binding of fluorescein isothiocyanate (FITC)-conjugated Annexin V to sperm plasma membranes. Annexin V monitors the translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane, which is one of the earliest features of membrane disintegration. For the second aim synthetic fluorogenic substrates for peptidases, proteinases, esterases, elastases and collagenases were applied. These substrates, CellProbe trade mark reagents consist of different peptide sequences, specific for the enzymes, and a fluorescein- or rhodamine 110-dye moiety. They enter the cells without previous membrane permeabilisation and exhibit fluorescence after cleavage depending on enzyme activity. The number of positive cells and the intensity of the fluorescence were determined by flow cytometric analysis comparing fresh spermatozoa with cryopreserved ones. Thirty-five semen samples collected from 35 donors were cryopreserved using the freezing medium TEST yolk buffer. All specimens showed normal spermiogram parameters. Twenty-five of the samples were used for detection of Annexin V-FITC binding and 10 semen samples for investigations of the intracellular enzymes. The Annexin V-assay applied two fluorescent dyes (Annexin V, AN and propidium iodide, PI) which led to three groups of spermatozoa (a) viable spermatozoa (AN V-negative and PI-negative), (b) dead spermatozoa (AN V-positive and PI-positive) and (c) cells with impaired but integer plasma membrane (AN V-positive and PI-negative). The percentage of vital Annexin V-negative spermatozoa (x +/- SEM) decreased significantly (p < 0.001) from fresh spermatozoa (51.6 +/- 3.1) to cryopreserved spermatozoa (26.6 +/- 2.2%) and was associated with their motility (57.9 +/- 1.9% motile fresh spermatozoa vs. 22.6 +/- 3.9% motile sperm after cryopreservation). Of the spermatozoa 28.2% were Annexin V-positive before and 44.4% after cryostorage even though they did not bind to PI. Thus, vital spermatozoa showed a disturbed membrane function indicating viability before as well as after cryostorage. Moreover, after cryopreservation the spermatozoal fluorescence increased applying substrates for butyryl esterase (p < 0.05), prolyl-aminopeptidase (p < 0.001) and val-lys-(VK)-cathepsin (p < 0.001). In contrast, the activities of fluorescein diacetate (FDA)- and FDA/sodium fluoride (NAF)-esterase (p < 0.05), ala-ala-pro-val-(AAPV)-elastase (p < 0.001), gly-pro-leu-gly-pro-(GPLGP)-collagenase (p < 0.05) and gly-gly-leu-(GGL)-subtilisin (p < 0.001) decreased after cryopreservation. The substrates for arg-gly-glut-ser-(RGES)-elastase, gly-phenyl-gly-ala-(GFGA)-collagenase and threo-pro-(TP)-cathepsin were not cleaved before as well as after cryostorage. In addition to the known effects of sperm cryopreservation our results showed two further alterations of human ejaculated spermatozoa: (a) disturbed plasma membrane function, which is not detectable by supravital staining and (b) a changed pattern of intracellular enzyme activities.
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PMID:Hidden effects of cryopreservation on quality of human spermatozoa. 1525 59

Blood vessel injury results in limited oxygen tension and diffusion leading to hypoxia, increased anaerobic metabolism, and elevated production of acidic metabolites that cannot be easily removed due to the reduced blood flow. Therefore, an acidic extracellular pH occurs in the local microenvironment of disrupted bone. The potential role of acidic pH and glu-leu-arg (ELR(+)) CXC chemokines in early events in bone repair was studied in human mesenchymal stem cells (hMSCs) treated with medium of decreasing pH (7.4, 7.0, 6.7, and 6.4). The cells showed a reciprocal increase in CXCL8 (interleukin-8, IL-8) mRNA levels as extracellular pH decreased. At pH 6.4, CXCL8 mRNA was induced >60x in comparison to levels at pH 7.4. hMSCs treated with osteogenic medium (OGM) also showed an increase in CXCL8 mRNA with decreasing pH; although, at a lower level than that seen in cells grown in non-OGM. CXCL8 protein was secreted into the medium at all pHs with maximal induction at pH 6.7. Inhibition of the G-protein-coupled receptor alpha, G(alphai), suppressed CXCL8 levels in response to acidic pH; whereas phospholipase C inhibition had no effect on CXCL8. The use of specific mitogen-activated protein kinase (MAPK) signal transduction inhibitors indicated that the pH-dependent increase in CXCL8 mRNA is due to activation of ERK and p38 pathways. The JNK pathway was not involved. NF-kappaB inhibition resulted in a decrease in CXCL8 levels in hMSCs grown in non-OGM. However, OGM-differentiated hMSCs showed an increase in CXCL8 levels when treated with the NF-kappaB inhibitor PDTC, a pyrrolidine derivative of dithiocarbamate.
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PMID:Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin-8), in human adult mesenchymal stem cells via the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways. 1827 43

Millions of teeth are saved each year by root canal therapy. Although current treatment modalities offer high levels of success for many conditions, an ideal form of therapy might consist of regenerative approaches in which diseased or necrotic pulp tissues are removed and replaced with healthy pulp tissue to revitalize teeth. Melanocortin peptides (alpha-MSH) possess anti-inflammatory properties in many acute and chronic inflammatory models. Our recent studies have shown that alpha-MSH covalently coupled to poly-l-glutamic acid (PGA-alpha-MSH) retains anti-inflammatory properties on rat monocytes. This study aimed to define the effects of PGA-alpha-MSH on dental pulp fibroblasts. Lipopolysaccharide (LPS)-stimulated fibroblasts incubated with PGA-alpha-MSH showed an early time-dependent inhibition of TNF-alpha, a late induction of IL-10, and no effect on IL-8 secretion. However, in the absence of LPS, PGA-alpha-MSH induced IL-8 secretion and proliferation of pulp fibroblasts, whereas free alpha-MSH inhibited this proliferation. Thus, PGA-alpha-MSH has potential effects in promoting human pulp fibroblast adhesion and cell proliferation. It can also reduce the inflammatory state of LPS-stimulated pulp fibroblasts observed in gram-negative bacterial infections. These effects suggest a novel use of PGA-alpha-MSH as an anti-inflammatory agent in the treatment of endodontic lesions. To better understand these results, we have also used the multilayered polyelectrolyte films as a reservoir for PGA-alpha-MSH by using not only PLL (poly-l-lysine) but also the Dendri Graft poly-l-lysines (DGL(G4)) to be able to adsorb more PGA-alpha-MSH. Our results indicated clearly that, by using PGA-alpha-MSH, we increase not only the viability of cells but also the proliferation. We have also analyzed at the nanoscale by atomic force microscopy these nanostructured architectures and shown an increase of thickness and roughness in the presence of PGA-alpha-MSH incorporated into the multilayered film (PLL-PGA-alpha-MSH)(10) or (DGL(G4)-PGA-alpha-MSH)(10) in accordance with the increase of the proliferation of the cells growing on the surface of these architectures. We report here the first use of nanostructured and functionalized multilayered films containing alpha-MSH as a new active biomaterial for endodontic regeneration.
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PMID:Nanostructured assemblies for dental application. 2050 54

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