Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:031995 (CXCL1)
 2,264 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine macrophage inflammatory protein-2 (MIP-2), a member of the alpha-chemokine family, is one of several proteins secreted by cells in response to lipopolysaccharide. Many of the alpha-chemokines, such as interleukin-8, gro-alpha/MGSA, and neutrophil activating peptide-2 (NAP-2), are associated with neutrophil activation and chemotaxis. We describe the expression, purification, and characterization of murine MIP-2 from Pichia pastoris. Circular dichroism spectroscopy reveals that MIP-2 exhibits a highly ordered secondary structure consistent with the alpha/beta structures of other chemokines. Recombinant MIP-2 is chemotactic for human and murine neutrophils and up-regulates cell surface expression of Mac-1. MIP-2 binds to human and murine neutrophils with dissociation constants of 6.4 nM and 2.9 nM, respectively. We further characterize the binding of MIP-2 to the human types A and B IL-8 receptors and the murine homologue of the IL-8 receptor. MIP-2 displays low-affinity binding to the type A IL-8 receptor (Kd > 120 nM) and high-affinity binding to the type B IL-8 receptor (Kd 5.7 nM) and the murine receptor (Kd 6.8 nM). The three-dimensional structure of IL-8 and sequence analysis of six chemokines (IL-8, gro-alpha, NAP-2, ENA-78, KC, and MIP-2) that display high-affinity binding to the IL-8 type B receptor are used to identify an extended N-terminal surface that interacts with this receptor. Two mutants of MIP-2 establish that this region is also involved in binding and activating the murine homologue of the IL-8 receptor. Differences in the sequence between IL-8 and related chemokines identify a unique hydrophobic/aromatic region surrounded by charged residues that is likely to impart specificity to IL-8 for binding to the type A receptor.
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PMID:Functional and receptor binding characterization of recombinant murine macrophage inflammatory protein 2: sequence analysis and mutagenesis identify receptor binding epitopes. 926 Feb 77

All 12 of the human CXC chemokine genes were physically mapped using gene-specific PCR primers and the GenBridge 4 radiation hybrid panel. Nine genes, PF4, PF4V1, GRO1, GCP2, PPBP, IL8, GRO2, GRO3, and SCYB5, were assigned within a 1.8-cR interval of one another on 4q. Two additional genes, MIG and INP10, map within 0.5 cR of each another and 6 cR distal to the above-mentioned group. The final gene, SDF1, is localized on 10q. Phylogenetic analyses of amino acid sequences revealed that SDF1 is the most divergent member and that the physically separated MIG-INP10 pair constitutes a distinct evolutionary lineage.
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PMID:Localization of the human CXC chemokine subfamily on the long arm of chromosome 4 using radiation hybrids. 946 7

A physical map of the CXC chemokine locus on chromosome 4 has been constructed by PCR analysis and PFGE mapping of YAC clones. The genes for IL8, GRO1, PPBP, PF4, SCYB5 (ENA-78) and SCYB6 (GCP-2) have been co-localized on a 335-kb genomic fragment. The GRO2 and GRO3 genes did not map within this region and based on analysis of a YAC contig overlapping IL8 we speculate that GRO2 and GRO3 map downstream of this region. We have also assigned the novel CXC chemokine gene, SCYB9B (alias H174/betaR1) to chromosome 4q21, upstream and within 12 kb of INP10. Like INP10 and MIG, INP10 and SCYB9B are arranged in a head to tail manner. The chromosomal arrangement of these genes appears to reflect the evolution of this multigene family and supports the theory that it arose by gene duplication.
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PMID:Physical mapping of the CXC chemokine locus on human chromosome 4. 1034 98

Recruitment of neutrophils into alveolar air spaces is an early event in the pathogenesis of pneumonia due to Streptococcus pneumoniae. This results from chemokines released by activated endothelial and epithelial cells and alveolar macrophages. Culture supernatants of 6 wild-type strains of S. pneumoniae, shown to contain choline-binding protein A (CbpA; clades A and B), induced release of chemokine CXCL8 from the human alveolar epithelial cell line A549, whereas a CbpA deletion mutant elicited significantly reduced CXCL8 release, compared with that of its isogenic parent (P<.01). Recombinant CbpA up-regulated expression of messenger RNA of CXCL8 and CCL2 but not of XCL1, CXCL10, CCL1, CCL3, CCL4, or CCL5 in A549 cells and induced increased secretion of CXCL8, CCL2, CXCL1, and CXCL5 in a dose- and time-dependent manner. CbpA also increased the expression of intercellular adhesion molecule 1 (CD54) by A549 cells. Thus, CbpA of S. pneumoniae induces the transcription and release of proinflammatory molecules by human alveolar epithelial cells.
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PMID:Choline-binding protein A of Streptococcus pneumoniae elicits chemokine production and expression of intercellular adhesion molecule 1 (CD54) by human alveolar epithelial cells. 1240 94

The ELR(+) CXC chemokines are critical for protective neutrophil responses to most bacterial infections, but nevertheless can contribute importantly to the pathogenic effects of many inflammatory responses. We recently engineered a series of high affinity CXCL8/IL-8 antagonists, one of which, CXCL8((3-73))K11R/G31P, binds very strongly to neutrophils via the CXCR1 and CXCR2. Herein we show in competitive 125I-ligand binding assays that bovine CXCL8((3-73))K11R/G31P has an affinity for neutrophils that is 2-3 orders of magnitude higher than that of CXCL8/IL-8. Furthermore, when used at approximately 0.5 nM, CXCL8((3-73))K11R/G31P inhibited by 50% the chemotactic responses of neutrophils to 129 nM CXCL8/IL-8, but it also blocked chemotactic responses to the alternate ELR-CXC chemokines CXCL1/GRO alpha and CXCL5/ENA-78. Furthermore, CXCL8((3-73))K11R/G31P could inhibit by 93-97% the spectrum of neutrophil chemotactic activities present within wash fluids from clinical bacterial pneumonia or experimental endotoxin-induced mastitis lesions. Finally, intramuscular or subcutaneous application of CXCL8((3-73))K11R/G31P (75 micro g/kg) reduced by up to 97% neutrophil infiltration into intradermal endotoxin challenge sites in cattle, and prevented their circulating neutrophils from responding to CXCL8/IL-8 or ENA-78 in vitro. This data thus encourages further investigation of the potential impact of this novel antagonist on ELR-CXC chemokine-driven inflammatory disorders.
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PMID:CXCL8((3-73))K11R/G31P antagonizes the neutrophil chemoattractants present in pasteurellosis and mastitis lesions and abrogates neutrophil influx into intradermal endotoxin challenge sites in vivo. 1240 56

Blood platelets play critical roles in hemostasis, providing rapid essential protection against bleeding and catalyzing the important slower formation of stable blood clots via the coagulation cascade. They are also involved in protection from infection by phagocytosis of pathogens and by secreting chemokines that attract leukocytes. Platelet function usually is activated by primary agonists such as adenosine diphosphate (ADP), thrombin, and collagen, whereas secondary agonists like adrenalin do not induce aggregation on their own but become highly effective in the presence of low levels of primary agonists. Current research has revealed that chemokines represent an important additional class of agonists capable of causing significant activation of platelet function. Early work on platelet alpha-granule proteins suggested that platelet factor 4, now known as CXCL4, modulated aggregation and secretion induced by low agonist levels. Subsequent reports revealed the presence in platelets of messenger RNA for several additional chemokines and chemokine receptors. Three chemokines in particular, CXCL12 (SDF-1), CCL17 (TARC), and CCL22 (MDC), recently have been shown to be strong and rapid activators of platelet aggregation and adhesion after their binding to platelet CXCR4 or CCR4, when acting in combination with low levels of primary agonists. CXCL12 can be secreted by endothelial cells and is present in atherosclerotic plaques, whereas CCL17 and CCL22 are secreted by monocytes and macrophages. Platelet activation leads to the release of alpha-granule chemokines, including CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), CCL17, CXCL1 (growth-regulated oncogene-alpha), CXCL5 (ENA-78), and CXCL8 (IL-8), which attract leukocytes and further activate other platelets. These findings help to provide a direct linkage between hemostasis, infection, and inflammation and the development of atherosclerosis.
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PMID:Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. 1285 50

Chemokines displayed on the luminal surface of blood vessels play pivotal roles in inflammatory and homeostatic leukocyte trafficking in vivo. However, the mechanisms underlying the functional regulation of chemokines on the endothelial cell surface remain ill-defined. A promiscuous chemokine receptor, the Duffy antigen receptor for chemokines (DARC), has been implicated in the regulation of chemokine functions. Here we show that DARC is selectively expressed at the mRNA and protein levels in the high endothelial venules (HEV) of unstimulated lymph nodes (LN). To examine the biological significance of DARC expression in HEV, we performed competitive binding experiments with 20 different chemokines. The results showed that DARC selectively bound distinct members of the pro-inflammatory chemokines such as CXCL1, CXCL5, CCL2, CCL5 and CCL7, but not lymphoid chemokines such as CCL21, CCL19, CXCL12 and CXCL13 that are normally expressed in HEV. CCL2 bound to DARC failed to induce a significant cytosolic [Ca(2+)] elevation in CCR2B-expressing cells, whereas the free form of CCL2 induced a distinct [Ca(2+)] elevation, suggesting that DARC down-regulates activities of pro-inflammatory chemokines upon binding. Targeted disruption of the gene encoding DARC did not induce any obvious changes in the cell number or leukocyte subsets in the peripheral and mesenteric LN. Neither did DARC deficiency significantly affect lymphocyte migration into LN. These results suggest that DARC may be a scavenger for pro-inflammatory chemokines, but not a presenting molecule for lymphoid chemokines at HEV and that it is probably functionally dispensable for lymphocyte trafficking to HEV-bearing lymphoid tissues under physiological conditions.
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PMID:A high endothelial venule-expressing promiscuous chemokine receptor DARC can bind inflammatory, but not lymphoid, chemokines and is dispensable for lymphocyte homing under physiological conditions. 1367 91

Transplantation of allogeneic grafts presents several challenges to the innate and adaptive immune systems including chemokine leukocyte recruitment, activation, and effector function. We defined the chemokines and receptors induced by the transplant procedure/ischemia injury, alloantigen and gene transfer vector administration in murine cardiac grafts. E1, E3 deleted AdRSVbetagal was transferred into grafts at the time of transplantation, grafts were harvested after 1-14 days, and a pathway-specific cDNA array was used to evaluate the levels of 67 chemokine and chemokine receptor genes. Transplantation resulted in ischemic injury and induction of a number of similar genes in both the syngeneic and allogeneic grafts, such as CXCL1 and CXCL5, which increased dramatically on day 1 and returned rapidly to baseline in the syngeneic grafts. Alloantigen stimulated the adaptive immune response and induced the presence of more inflammatory genes within the grafts, particularly at later time points. The adenovirus vector induced a broader panel of genes, among them potent inflammatory chemokines CXCL9 and CXCL10, that are induced earlier or more strongly compared with alloantigen stimulation alone. As alloantigen and adenovirus vectors both induce similar sets of genes, targeting these molecules may not only inhibit alloimmunity, but also enhance the utility of the gene transfer vector.
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PMID:Differential chemokine and chemokine receptor gene induction by ischemia, alloantigen, and gene transfer in cardiac grafts. 1451 Jun 95

CXCL5 (epithelial-cell-derived neutrophil-activating protein (ENA-)78) is a CXC-chemokine that specifically acts on neutrophils. To obtain insight into the extent of local presence and action of CXCL5 during bacterial meningitis, we measured its concentrations in cerebrospinal fluid (CSF) of patients with culture-proven bacterial meningitis (n=14), aseptic meningitis (n=6), and controls (n=32) and compared these results with levels of other CXC-chemokines, CXCL8- (interleukin-8) and CXCL1-related oncogene (growth-related oncogene (GRO)-alpha). Patients with bacterial meningitis had profoundly elevated CSF concentrations of all three chemokines. CXCL5 was not detectable in patients with aseptic meningitis or control subjects. CSF from patients with bacterial meningitis exerted chemotactic activity towards neutrophils, which was partially inhibited by neutralizing antibodies against CXCL5 and CXCL8, but not CXCL1. CSF from controls exerted minor chemotactic activity, which could be strongly enhanced by the addition of recombinant CXCL5, CXCL8 or CXCL1. During bacterial meningitis, CXCL5 is elevated in CSF, where it is involved in the recruitment of neutrophils to the central nervous system.
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PMID:Chemotactic activity of CXCL5 in cerebrospinal fluid of children with bacterial meningitis. 1464 41

Aside from its mechanical barrier function, bronchial epithelium plays an important role both in the host defense and in the pathogenesis of inflammatory airway disorders. To investigate its role in lung defense, the effect of a bacterial cell wall protein, the outer membrane protein A from Klebsiella pneumoniae (kpOmpA) on bronchial epithelial cells (BEC) was evaluated on adhesion molecule expression and cytokine production. Moreover, the potential implication of this mechanism in kpOmpA-induced lung inflammation was also determined. Our in vitro studies demonstrated that kpOmpA strongly bound to BEAS-2B cells, a human BEC line, and to BEC primary cultures, resulting in NF-kappaB signaling pathway activation. Exposure to kpOmpA increased ICAM-1 mRNA and cell surface expression, as well as the secretion of IL-6, CXC chemokine ligand (CXCL)1, CXCL8, C-C chemokine ligand 2, CXCL10 by BEAS-2B cells, and BEC primary cultures (p < 0.005). We analyzed in vivo the consequences of intratracheal injection of kpOmpA to BALB/c mice. In kpOmpA-treated mice, a transient neutrophilia (with a maximum at 24 h) was observed in bronchoalveolar lavage and lung sections. In vivo kpOmpA priming induced bronchial epithelium activation as evaluated by ICAM-1 and CXCL1 expression, associated with the secretion of CXCL1 and CXCL5 in bronchoalveolar lavage fluids. In the lung, an increased level of the IL-6, CXCL1, CXCL5, CXCL10 mRNA was observed with a maximum at 6 h. These data showed that kpOmpA is involved in host defense mechanism by its ability to activate not only APC but also BEC, resulting in a lung neutrophilia.
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PMID:Outer membrane protein A from Klebsiella pneumoniae activates bronchial epithelial cells: implication in neutrophil recruitment. 1466 73


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