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)

Studies of human neutrophil IL-8 receptors, CXCR1 and CXCR2, have shown that the two receptors are differentially regulated by ELR(+)-CXC chemokines, that they differ functionally and may have diverse roles in mediating the inflammatory process. To elucidate the role of CXCR1 and CXCR2 in inflammation and to delineate the basis for the divergent regulation of these receptors by IL-8 and NAP-2, we characterized the IL-8- and NAP-2-induced mechanisms regulating the expression of each receptor, focusing on receptor internalization and recycling. Using HEK 293 cell transfectants, IL-8 was shown to induce significantly higher levels of CXCR2 internalization than NAP-2. Moreover, although CXCR2 bound IL-8 and NAP-2 with similarly high affinity, IL-8 functionally competed with and displaced NAP-2, and prompted high levels of internalization, similar to those induced by IL-8 alone. In a system providing an identical cellular milieu for reliable comparisons between CXCR1 and CXCR2, we have shown that the mechanisms controlling the internalization of CXCR1 diverge from those regulating CXCR2 internalization. Whereas IL-8-induced internalization of CXCR1 was profoundly dependent on a region of the carboxyl terminus expressing six phosphorylation sites, internalization of CXCR2 was primarily regulated by a membrane proximal domain of the carboxyl terminus that does not express phosphorylation sites. Analysis of receptor re-expression on the plasma membrane indicated that at early time points following removal of free ligand and incubation of the cells at 37 degrees C, receptor recycling accounted for recovery of CXCR1 and CXCR2 expression, whereas at later time points other processes may be involved in receptor re-expression. Phosphorylation-independent mechanisms were shown to direct both receptors to the recycling pathway. The differential control of CXCR1 vs CXCR2 internalization by IL-8 and NAP-2, as well as by phosphorylation-mediated mechanisms, suggests that a chemokine- and receptor-specific mode of regulation of internalization may contribute to the divergent activities of these receptors.
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PMID:Differential modes of regulation of cxc chemokine-induced internalization and recycling of human CXCR1 and CXCR2. 1062 25

Toll-like receptor 2 (TLR2) has been recognized to mediate cell signaling in response to peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria. The mechanism by which TLR2 recognizes PGN is unknown. It is not even clear whether TLR2 directly binds to PGN. In this study, we generated a soluble form of recombinant TLR2 (sTLR2) possessing only its putative extracellular domain by using the baculovirus expression system to examine the direct interaction between sTLR2 and PGN. sTLR2 bound avidly to insoluble PGN (iPGN) from Staphylococcus aureus coated onto microtiter wells in a concentration-dependent manner. In contrast, sTLR2 exhibited a very weak binding to lipopolysaccharide. iPGN cosedimented sTLR2 after the mixture of iPGN and sTLR2 had been incubated and centrifuged. sTLR2 partially attenuated the iPGN-induced NF-kappaB activation in TLR2-transfected HEK 293 cells and the iPGN-induced IL-8 secretion in U937 cells. One of anti-human TLR2 monoclonal antibodies, which blocked iPGN-induced NF-kappaB activation in TLR2-transfected cells, inhibited the binding of sTLR2 to iPGN. In addition, we found that sCD14 interacted with sTLR2 and increased the binding of sTLR2 to iPGN. From these results, we conclude that the extracellular TLR2 domain directly binds to PGN.
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PMID:The extracellular toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus. 1198 1

Periodate-oxidized ATP (oATP), which covalently modifies nucleotide-binding proteins, can significantly attenuate proinflammatory signaling. Although the P2X7 nucleotide receptor (P2X7R) is irreversibly antagonized by oATP, it is unclear whether anti-inflammatory actions of oATP are predominantly mediated via its actions on P2X7R. Here, we describe inhibitory effects of oATP on proinflammatory responses in three human cell types that lack expression of P2X7R: human umbilical vein endothelial cells (HUVEC), HEK293 cells, and 1321N1 astrocytes. oATP decreased by 40-70% the secretion of interleukin (IL)-8 stimulated by tumor necrosis factor-alpha (TNF-alpha) in all three cell types, by IL-1beta in HUVEC and 1321N1 cells, and by endotoxin in HUVEC. Attenuation of TNF-alpha-stimulated IL-8 secretion by oATP was similar in wild-type HEK cells or HEK cells stably expressing recombinant P2X7R. oATP also attenuated cytokine-stimulated expression of nuclear factor-kappaB-luciferase reporter genes expressed in HEK or 1321N1 cells, but did not affect the rapid downregulation of IkappaB. oATP had no effect on uridine triphosphate-induced activation of native P2Y2 receptors in HEK cells, but reduced the potency and efficacy of ADP as an agonist of native P2Y1 receptors. However, inhibition of P2Y1 receptors with the specific antagonist MRS2216 did not mimic the effects of oATP on TNF-alpha-stimulated IL-8 secretion. Although 1321N1 astrocytes lack expression of any known P2 receptor subtypes, oATP markedly inhibited ecto-ATPase activity in these cells, resulting in a significant accumulation of extracellular ATP. In summary, oATP can attenuate proinflammatory signaling by mechanisms independent of the expression or activation of known P2 receptor subtypes.
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PMID:Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms. 1452 40

Triple helix-forming oligonucleotides (TFOs) that specifically bind to double-stranded DNA sequences can be rationally designed, while intracellular delivery of single stranded RNA TFOs has not yet been studied in detail. In this report, we demonstrate gene and sequence-specific inhibition of MCP-1 gene expression due to interference of intracellular-generated single-stranded RNA (CU-TFO) with an overlapping SP-1/AP-1 target. Binding of synthetic 19-nucleotide (19-nt) CU-TFO to the MCP-1 promoter duplex was verified by triplex blotting. Furthermore, we confirmed binding of a 1.1-kb fusion transcript containing the 19-nt pyrimidine CU sequence to a plasmid-encoded MCP-1 promoter target duplex at pH 7.0. In tumour necrosis factor-alpha-stimulated HEK cells, CU-TFOs inhibited MCP-1 protein release by 76 +/- 10.2% compared to intracellular-generated control oligonucleotides. Interleukin-8 as a control target gene was not affected by CU-TFO, confirming both highly specific and effective chemokine gene repression by transfectable TFO-shuttle vectors.
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PMID:Interference with MCP-1 gene expression by vector generated triple helix-forming RNA oligonucleotides. 1572 71

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young infants worldwide. Previous studies have reported that the induction of interleukin-8/CXCL8 and RANTES/CCL5 correlates with disease severity in humans. The production of these chemokines is elicited by viral replication and is NF-kappaB dependent. RSV, a negative-sense single-stranded RNA virus, requires full-length positive-sense RNA for synthesis of new viral RNA. The aim of our studies was to investigate whether active viral replication by RSV could evoke chemokine production through TLR3-mediated signaling pathways. In TLR3-transfected HEK 293 cells, live RSV preferentially activated chemokines in both a time- and dose-dependent manner compared to vector controls. RSV was also shown to upregulate TLR3 in human lung fibroblasts and epithelial cells (MRC-5 and A549). Targeting the expression of TLR3 with small interfering RNA decreased synthesis of IP-10/CXCL10 and CCL5 but did not significantly reduce levels of CXCL8. Blocking the expression of the adapter protein MyD88 established a role for MyD88 in CXCL8 production, whereas CCL5 synthesis was found to be MyD88 independent. Production of CCL5 by RSV was induced directly through TLR3 signaling pathways and did not require interferon (IFN) signaling through the IFN-alpha/beta receptor. TLR3 did not affect viral replication, since equivalent viral loads were recovered from RSV-infected cells despite altered TLR3 expression. Taken together, our studies indicate that TLR3 mediates inflammatory cytokine and chemokine production in RSV-infected epithelial cells.
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PMID:Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression. 1573 Dec 29

We recently showed that oligomerization of CD40 molecules on cell surface leads to disulfide-linked CD40/CD40 dimer formation, an event that is necessary for CD40-induced B7-2 expression in human B cells. Here, we demonstrate that CD40/CD40 dimers formation also occurs in different cell types such as T24 bladder cancer cells and CD40-transfected HEK 293 cells. Disulfide bonds mediate the formation of CD40/CD40 homodimers in CD40-activated cells. To determine the potential residue(s) involved in disulfide bonds formation and subsequent CD40-induced IL-8 expression, we generated a CD40 mutant in which the extracellular cysteine 6 was replaced by a glutamine (CD40-C6Q). CD40-induced IL-8 mRNA expression and protein synthesis were studied in stably transfected HEK 293 cells that were sorted out along with similar levels of expression of wild type (CD40-WT) and CD40-C6Q molecules. In contrast to cells expressing CD40-WT protein, disulfide-linked CD40/CD40 dimer formation was completely abolished in HEK 293 cells expressing CD40-C6Q proteins. Abolishment of disulfide-linked CD40/CD40 dimers in these transfected cells was sufficient to inhibit CD40-induced mRNA expression and secretion of IL-8. This study identifies the extracellular cysteine 6 of CD40 molecules as a potential molecular target to disrupt the expression of CD40-induced pro-inflammatory cytokines by epithelial cells.
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PMID:Requirement of the extracellular cysteine at position six for CD40/CD40 dimer formation and CD40-induced IL-8 expression. 1582 65

We examined the role of cysteine (Cys) residues present in chemokine receptor CXCR2 for proper surface expression, dimerization, signaling, and chemotaxis. To address this issue, serine or leucine residues were substituted for Cys, generating nine CXCR2 mutants transiently expressed in HEK cells. Single substitution of Cys residues present in the three extracellular loops (C119L, C196L, C286S) or in the seventh-transmembrane (TM) domain (C308L) abolished CXCL8 agonist binding, while no Cys substitution abolished surface receptor expression. We have previously demonstrated that CXCR2 dimerizes under reducing conditions, due to hydrophobic interactions that involve TM3 regions, and here we show that the dimer/monomer CXCR2 ratio drastically increases when analyzed under non-reducing conditions. We report that none of the Cys-deficient CXCR2 mutants abolishes receptor dimerization, demonstrating that Cys-Cys bonds are not the exclusive determinant of CXCR2 dimerization. Furthermore, both wt- and Cys-mutated CXCR2 dimers are expressed at the cell surface, indicating that receptor dimers are efficiently transferred at the plasma membrane. We also show that every Cys substitution in CXCR2, including those that still bind CXCL8, results in an impairment of receptor activity, analyzed as cell chemotaxis and intracellular signaling, suggesting that some structural requirement is likely fulfilled by Cys presence.
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PMID:Cysteine residues are critical for chemokine receptor CXCR2 functional properties. 1592 27

The complex formation of lipopolysaccharide (LPS) with chitosan (Ch) was demonstrated using sedimentation velocity analysis in the analytical ultracentrifuge, centrifugation in glycerol gradient and isopicnic centrifugation in cesium chloride. An addition of Ch to the Escherichia coli and Yersinia pseudotuberculosis LPS solutions was found to result in formation of the stable LPS-Ch complexes. The interaction is a complicated process and depends on time and reaction temperature, as well as on the molecular weight of chitosan. A stable LPS-Ch complex could be formed only after preliminary incubation of the initial components at an elevated temperature (37 degrees C). It should be noted that process of LPS complexation with Ch is accompanied by additional dissociating of LPS. The complex formation was shown to be a result not only of ionic binding, but also of other types of interactions. The interaction of Ch with LPS was shown to modulate significantly the biological activity of LPS. The LPS-Ch complex (1:5 w/w) was shown to possess much lower toxicity in a comparison with the parent LPS at injection to mice in the similar concentration. The LPS-Ch complex was shown to maintain an ability to induce of IL-8 and TNF, but induction of IL-8 and TNF biosynthesis by the LPS-Ch complex was lower than that by the parent LPS. The complex LPS-Ch, similarly to the parent LPS, was found stimulated the formation of the IL-8 in the dose-dependent manner in the human embryonal kidney cells (HEK 293 cells) transfected with TLR4 in combination with MD2.
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PMID:Forming and immunological properties of some lipopolysaccharide-chitosan complexes. 1618 24

Theiler's murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) induces a demyelinating disease similar to human multiple sclerosis. TMEV infection results in activation of various chemokine and cytokine genes that are important in the initiation of an inflammatory response. We have previously shown that the production of these chemokines and cytokines in astrocytes is induced via the NF-kappaB pathway following TMEV and Coxsackie virus infection. In this study, we investigated whether the NF-kappaB-dependent inflammatory responses after TMEV infection is triggered through TLR3 and/or TLR7. The activation of NF-kappaB or IRF/ISRE, as well as the production of both MCP-1/CCL2 and IL-8/CXCL8, was observed in only TLR3-transfected HEK 293 cells, but not in TLR7-tranfected cells. The potential involvement of TLR3 in mouse embryonic fibroblasts and primary astrocytes was further investigated following transfection with wildtype or dominant negative form of TLRs and MyD88, as well as astrocytes from TLR3- and MyD88-deficient mice. Similarly, the activation of transcription factors and chemokine genes is induced in these mouse cells through primarily TLR3 signaling pathway, but not TLR7 or other MyD88-mediated pathways following TMEV infection. However, the TLR3-mediated cellular activation does not appear to affect the level of viral replication in astrocytes. These results strongly suggest that TLR3-signaling by TMEV alone is sufficient to induce the initial inflammatory cytokine responses that could be very important for the outcome of virus-induced encephalitis and/or demyelinating diseases, such as multiple sclerosis.
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PMID:Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3. 1658 93

IL-8/CXCL8 plays a critical role in the trafficking and activation of neutrophils via its receptors, CXCR1 and CXCR2, in humans. CXCR1 is highly selective for IL-8, whereas CXCR2 is activated by all CXC chemokines with an ELR motif. In mice and rats, neither IL-8 nor CXCR1 is present, making it difficult to evaluate the in vivo roles of the IL-8/CXCR1 interactions. We previously demonstrated the presence of IL-8 in the guinea pig (gp), suggesting that its specific receptor CXCR1 is also present in this species. Here, we obtained two gp genomic DNA clones, clones 8 and 10, coding for the potential orthologues of CXCR1 and CXCR2, respectively. Transcripts for these genes were expressed in neutrophils, but not in macrophages. Functionally, both gp and human (h) IL-8 induced cell migration and ERK phosphorylation in HEK 293 cells expressing either receptor, whereas hGRO activated only cells expressing the clone 10 protein, confirming that clone 8 indeed coded for gpCXCR1. 125I-labeled hIL-8 bound to gpCXCR1 and addition of unlabeled hIL-8 completely abolished the binding; however, unlabeled gpIL-8 failed to compete against 125I-labeled hIL-8, strongly suggesting that the avidity of hIL-8 to gpCXCR1 is higher than that of gpIL-8. Identification and characterization of CXCR1 in the guinea pig will allow us to use this small animal model to evaluate the role of the IL-8/CXCR1 interactions and to examine the efficacy of CXCR1 antagonists in vivo.
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PMID:Cloning and characterization of guinea pig CXCR1. 1671 33


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