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)

The Duffy blood group antigen has been postulated to be a receptor on red blood cells (RBCs) for the malarial parasite Plasmodium vivax and a promiscuous receptor for the chemokine superfamily of inflammatory proteins. Recently, the Duffy antigen glycoprotein D cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). We have analyzed the binding properties of the cloned Duffy antigen. Duffy-antigen cDNAs expressed in human embryonic kidney cells produced cell-surface proteins that reacted with two known anti-Duffy monoclonal antibodies. Direct ligand binding and displacement experiments using recombinant chemokine proteins also show that the cloned Duffy protein is the RBC chemokine receptor. Radiolabeled chemokines of both the C-C (RANTES and MCP-1) and C-X-C (IL-8 and MGSA/gro) subclasses bound reversibly to transfected cells with dissociation constants in the nanomolar range. Chemokines of either class displaced heterologous chemokines, indicating that they were competing for a single site on the transfected cells. Although the chemokines bound to the transfected cells with high affinity, there was no evidence for signal transduction, as measured by transient increases in intracellular calcium ion concentration, through the Duffy antigen/RBC chemokine receptor in transfected cells. Lastly, we have performed a computer analysis on the amino acid structure of the Duffy antigen/RBC chemokine receptor. Although the cloned Duffy antigen has been postulated to be a nine-transmembrane-spanning receptor, our analysis suggests that the molecule most likely belongs to the seven-transmembrane-spanning receptor superfamily and is therefore similar to other chemokine receptors previously identified.
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PMID:Functional and biochemical analysis of the cloned Duffy antigen: identity with the red blood cell chemokine receptor. 751 17

The human erythrocyte chemokine receptor has recently been shown to be identical to the Duffy blood group antigen and is expressed in multiple organs, including kidney. Here we have examined the molecular properties of the renal isoform. Immunoblot analysis of erythrocyte and kidney detergent lysates, with a monoclonal antibody (Fy6) to the Duffy antigen, revealed that the renal isoform had a molecular mass of 43-45 kD, which could be distinguished from that observed in erythroid cells (38-47 kD). Chemical cross-linking of kidney membranes to 125I-melanoma growth stimulatory activity (MGSA) indicated that the renal chemokine receptor had a molecular mass of 38-45 kD. Binding of 125I-labeled MGSA to kidney membranes was competitively inhibited by the addition of unlabeled MGSA, IL-8, regulated on activation, normal T expressed and secrted, and monocyte chemotactic protein-1. Scatchard analysis of MGSA binding showed that the chemokine receptor from renal tissues had a binding affinity of 3.5 nM similar to that observed for the erythroid isoform (5-10 nM). The primary structure of the renal chemokine receptor predicted from the nucleotide sequence of cDNA from renal tissues is identical to that reported for the erythroid isoform. Immunocytochemical staining of kidney with Fy6 localized expression to endothelial cells present in postcapillary venules. These studies implicate the Duffy antigen/chemokine receptor in the complex interactions between postcapillary endothelial cells and granulocytes, which are modulated by pro-inflammatory chemokines.
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PMID:Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen. 808 83

IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.
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PMID:Expression of chemokine receptors by subsets of neurons in the central nervous system. 905 25

The Duffy Antigen Receptor for Chemokines (DARC) belongs to a family of erythrocyte chemokine receptors that bind C-X-C and C-C chemokines such as interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1) and regulated-on-activation, normal T cell-expressed and -secreted (RANTES), but not macrophage inflammatory protein 1 alpha (MIP-1 alpha) or MIP-1 beta. DARC has also been identified to a receptor for malaria parasites Plasmodium vivax and Plasmodium knowlesi. In the present study, we show that HIV-1 binds to RBCs from Caucasian individuals via DARC making RBCs able to transmit HIV to peripheral blood mononuclear cells (PBMCs). Furthermore, binding of HIV-1 particles to RBCs is inhibited by treating these cells with recombinant RANTES, but not with recombinant MIP-1 alpha prior to their incubation with HIV-1. This finding suggests that RBCs may function as a reservoir for HIV-1 or as a receptor for the entry of HIV-1 into CD4-cell subsets as well as neurons or endothelial cells.
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PMID:Binding of HIV-1 to RBCs involves the Duffy antigen receptors for chemokines (DARC). 992 12

The accumulation of cytokines in stored red blood cell concentrates (RCCs) has been implicated as a potential cause of transfusion reactions associated with the use of such products. At present, it is unclear whether there is any link between residual leukocyte and/or platelet content with cytokine levels in various RCCs. In this study, we have therefore assessed cytokine levels of leukocyte (e.g., IL8) and platelet (e.g., RANTES, TGF-beta1) origin in supernatants of RCCs prepared by the plasma reduced method or by depletion of the buffy coat. We have also assessed whether the Duffy antigen receptor (DARC, a promiscuous receptor for some chemokines) has any role in the diminution of cytokine levels in stored blood components by comparing cytokine levels in stored plasma reduced RCCs derived from both DARC +ve and DARC -ve individuals. In addition, comparison of filtered and non-filtered products of the same origin has also been conducted. Results showed that supernatants from DARC -ve concentrates contained higher levels of IL-8 up to days 14/15 of storage compared with DARC +ve RCCs. However, at later time points, similar levels of IL-8 were observed in RCCs regardless of their Duffy receptor status. For TGF-beta1 and RANTES, no significant difference in the levels of these cytokines was detected between DARC +ve and DARC -ve concentrates. Removal of leukocytes and platelets by conventional leukocyte filtration significantly reduced the accumulation of cytokines. Buffy coat reduced RCCs contained minimal amounts of IL-8 and TGF-beta1 but no RANTES. We conclude therefore, that the levels of cytokines in the supernatants of RCCs stored at 4 degrees C are related mainly to their leucocyte and platelet content.
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PMID:Cytokine accumulation in stored red cell concentrates: effect of buffy-coat removal and leucoreduction. 1092 48

The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL-8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL-8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso-occlusive crises. The differences in mean IL-8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0.0001 and 0.04 respectively). The mean IL-8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 +/- 1400 pg/ml vs. 1900 +/- 470 pg/ml, P = 0.03). Granulocyte colony-stimulating factor (G-CSF) (2000 +/- 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL-8 and other chemokines. These findings suggest that IL-8 and G-CSF may play a role in the development of the ACS and the complications associated with it.
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PMID:Elevated serum and bronchoalveolar lavage fluid levels of interleukin 8 and granulocyte colony-stimulating factor associated with the acute chest syndrome in patients with sickle cell disease. 1112 88

Chemokines represent a family of potent biological mediators. Within the group of receptors mediating their effects, a promiscuous receptor has been found which is able to bind and inactivate diverse chemokines of both C-C and C-X-C families. It is co-localized with blood group antigens of the Duffy system on the same glycoprotein and expressed on red blood cells as well as post-capillary blood vessels. In the present study three aspects of Duffy pathophysiology were studied: firstly the amount of IL-8 and RANTES binding to red blood cells and its correlation to disease activity of psoriatic patients, secondly the distribution of Duffy phenotype among psoriatic patients and thirdly the expression of Duffy antigen in normal vs psoriatic skin. Red blood cells from psoriatic patients (n=50) were lysed by triton X (1%) and supernatants tested in IL-8- and RANTES sandwich-ELISA. Duffy phenotype of psoriatic patients (n=50) was assessed by typing red blood cells with specific antisera in indirect Coombs technique. For immunohistochemical detection in normal and psoriatic skin (n=10 respectively) a specific monoclonal antibody (Fy6) was used. Neither IL-8- nor RANTES-levels on red blood cells correlated to disease activity and distribution of Duffy phenotype in psoriatics was not significantly altered when compared to the normal population. Furthermore, Duffy antigen was expressed in a similar pattern in normal and psoriatic skin at all parts of vasculature, albeit much more abundantly in diseased skin. Altogether, chemokine binding to red blood cells seems of minor importance in psoriasis. However, Duffy antigen together with other binding mechanisms like proteoglycans may play a role at local level by binding locally produced chemokines. Thus biological effects of chemokines are both restricted and focussed to dermal tissue.
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PMID:The role of the Duffy antigen-related chemokine receptor in psoriasis vulgaris. 1216 May 21

The Duffy Ag expressed on RBCs, capillaries, and postcapillary venular endothelial cells binds selective CXC and CC chemokines with high affinity. Cells transfected with the Duffy Ag internalize but do not degrade chemokine ligand. It has been proposed that Duffy Ag transports chemokines across the endothelium. We hypothesized that Duffy Ag participates in the movement of chemokines across the endothelium and, by doing so, modifies neutrophil transmigration. We found that the Duffy Ag transfected into human endothelial cells facilitates movement of the radiolabeled CXC chemokine, growth related oncogene-alpha/CXC chemokine ligand 1 (GRO-alpha/CXCL1), across an endothelial monolayer. In addition, neutrophil migration toward GRO-alpha/CXCL1 and IL-8 (IL-8/CXCL8) was enhanced across an endothelial monolayer expressing the Duffy Ag. Furthermore, GRO-alpha/CXCL1 stimulation of endothelial cells expressing the Duffy Ag did not affect gene expression by oligonucleotide microarray analysis. These in vitro observations are supported by the finding that IL-8/CXCL8-driven neutrophil recruitment into the lungs was markedly attenuated in transgenic mice lacking the Duffy Ag. We conclude that Duffy Ag has a role in enhancing leukocyte recruitment to sites of inflammation by facilitating movement of chemokines across the endothelium.
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PMID:Duffy antigen facilitates movement of chemokine across the endothelium in vitro and promotes neutrophil transmigration in vitro and in vivo. 1273 73

The aim of the study was to compare the ability of the human Duffy antigen to bind homeostatic and inflammatory chemokines. Homeostatic chemokines did not bind to the Duffy antigen on erythrocytes with high affinity. In contrast, 60% of inflammatory chemokines bound strongly to Duffy, with no obvious preference for CXC or CC classes. It was investigated if this binding profile was reflected in the binding pattern of endothelial cells. Two examples of homeostatic (125I-CXCL12 and 125I-CCL21) and inflammatory (125I-CXCL8 and 125I-CCL5) chemokines were incubated with human synovia. In agreement with the erythrocyte binding data, intense specific signals for CXCL8 and CCL5 binding were found on endothelial cells, whereas CXCL12 and CCL21 showed only weak binding to these cells. Our study provides evidence that the human Duffy antigen binds selected inflammatory, but not homeostatic, chemokines and that this binding pattern is reflected by endothelial cells within inflamed and non-inflamed tissue.
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PMID:The human Duffy antigen binds selected inflammatory but not homeostatic chemokines. 1535 76

Plasmodium vivax is one of four Plasmodium species that cause human malaria. P. vivax and a related simian malaria parasite, Plasmodium knowlesi, invade erythrocytes by binding the Duffy antigen/receptor for chemokines (DARC) through their respective Duffy binding proteins. Here we show that tyrosines 30 and 41 of DARC are modified by addition of sulphate groups, and that the sulphated tyrosine 41 is essential for association of the Duffy binding proteins of P. vivax (PvDBP) and P. knowlesi (PkDaBP) with DARC-expressing cells. These sulphated tyrosines also participate in the association of DARC with each of its four known chemokine ligands. Alteration of tyrosine 41 to phenylalanine interferes with MCP-1, RANTES and MGSA association with DARC, but not with that of IL8. In contrast, alteration of tyrosine 30 to phenylalanine interferes with the association of IL8 with DARC. A soluble sulphated amino-terminal domain of DARC, but not one modified to phenylalanine at residue 41, can be used to block the association of PvDBP and PkDaBP with red blood cells, with an IC50 of approximately 5 nM. These data are consistent with a role for tyrosine sulphation in the association of many or most chemokines with their receptors, and identify a key molecular determinant of erythrocyte invasion by P. vivax.
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PMID:Sulphated tyrosines mediate association of chemokines and Plasmodium vivax Duffy binding protein with the Duffy antigen/receptor for chemokines (DARC). 1572 May 50


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