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)

Several cytokines have been suggested to play a regulatory action on the neoplastic clone of patients with B-cell chronic lymphocytic leukemia (B-CLL) by interfering in the differentiation, proliferation, or death/survival pathways. Interleukin-8 (IL-8) is a chemoattractant protein constitutively expressed at the mRNA level and released by B-CLL cells. In view of the presence of the IL-8 receptor mRNA and of specific IL-8 binding, confirmed also by Scatchard analysis using 125I-IL-8, the study was extended to evaluate the possible regulatory role of this cytokine on B-CLL cells. IL-8 failed to show any in vitro proliferative effect on leukemic B-CLL cells. By contrast, the propidium iodide (PI) staining of the DNA content showed that IL-8 could prolong the survival of resting B-CLL cells in 11 of 16 cases studied. In the remaining 5 cases, 90.6% +/- 4.39% SD of the cells after culture remained viable and IL-8 could exert a significant death protection action after pretreatment with 10(-4) mol/L hydrocortisone, which reduced the percentage of viable B-CLL cells. The dose range of IL-8 capable of inducing the prolonging survival effect is comparable with the levels of IL-8 released constitutively by B-CLL cells, indicating that the death protection action is exerted at physiologic doses. The in vitro rescue from death induced by IL-8 is reflected by an increased expression of bcl-2 mRNA in B-CLL cases incubated in the presence of IL-8. These findings were further confirmed at the protein level, because in B-CLL cells that displayed a bimodal bcl-2 intracytoplasmatic protein expression IL-8 was capable of upmodulating the bcl-2high expression peak. The potential autocrine regulatory action exerted by IL-8 is supported by the evidence that exogenous IL-8 can upregulate IL-8 mRNA in B-CLL cells. These results, together with the demonstration that antibody-mediated neutralization of endogenous IL-8 could induce a significant in vitro reduction in the number of living cells, further support the hypothesis that, in B-CLL, the physiologic doses of IL-8 released constitutively by the leukemic clone may play an autocrine role in the process of cell accumulation characteristic of this disease.
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PMID:Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion. 863 99

Interleukin-8 (IL-8), one of the major mediators of the inflammatory response, belongs to a family of chemokines that includes NAP-2 (neutrophil-activating peptide-2) and Gro-alpha and whose biological activities are directed to a great extent toward neutrophils. Two distinct receptors have been described with overlapping, but not identical, binding affinities for IL-8, NAP-2, and Gro-alpha. This study was designed to examine the intracellular pathways activated upon the occupation of each of the IL-8 receptors (IL-8R). The formation of a physical coupling between IL-8 receptors and the alpha-subunit of heterotrimeric G proteins was tested in neutrophils by examining the presence of the former in anti-Galpha immune precipitates. The addition of IL-8 to a suspension of human neutrophils led to a time-dependent detection of IL-8 in anti-Gi2alpha (raised against amino acids 159-168 (LERIAQSDYI) of Gi2alpha) and anti-Gtalpha (raised against the COOH-terminal 10 amino acids (KENLKDCGLF) of Gtalpha), but not anti-Gq, immunoprecipitates. Similar results were obtained in human 293 cells stably transfected with IL-8RA or IL-8RB. The peptide derived from the COOH-terminal sequence of Gt inhibited the co-immunoprecipitation of IL-8R and Gi observed in response to the anti-Gtalpha and anti-Gi2alpha antibodies. On the other hand, the Gi2alpha peptide only inhibited the immunoprecipitation induced by the anti-Gi2alpha antibody. Peptides derived from Gi1alpha or Gi3alpha had no effect in this assay. The introduction of the anti-Gi2alpha or anti-Gtalpha antibodies or their neutralizing peptides, but not the Gi1alpha or Gi3alpha peptides, into 293 IL-8RA or 293 IL-8RB cells completely blocked the calcium responses obtained upon stimulation with IL-8. These results demonstrate that the occupation of either type of IL-8 receptor leads to a physical coupling to the alpha-subunit of Gi2. In addition, the use of the subunit-specific peptides identified two functionally important but distinct regions of Gialpha, one involved in receptor/Gialpha interaction (KENLKDCGLF) and the other mediating downstream signal transmission (LERIAQSDYI). Finally, the results of this study also validate the use of the transfected 293 cell line as a model for the study of the signal transduction pathway(s) initiated by IL-8.
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PMID:Physical association of Gi2alpha with interleukin-8 receptors. 866 98

Two monoclonal antibodies, anti-IL8R1 and anti-IL8R2, raised against both interleukin 8 receptors (IL-8R) of human neutrophils, IL-8R1 and IL-8R2, were used to study individual receptor functions after stimulation with IL-8, GRO alpha, or NAP-2. Efficacy and selectivity of the antibodies were tested in Jurkat cells transfected with cDNA coding for one or the other receptor. The binding of 125 I labeled IL-8 and IL-8-induced changes of the cytosolic free Ca2+ concentration were inhibited by anti-IL8RI in cells expressing IL-8R1 and by anti-IL8R2 in cells expressing IL-8R2. In human neutrophils, release of elastase was observed after stimulation with IL-8 or GRO alpha. The response to IL-8 was inhibited slightly by anti-IL8R1 and more substantially when both monoclonal antibodies were present, while the response to GRO alpha was inhibited by anti-IL8R2 but was not affected by anti-IL8R1. These results indicate that both IL-8 receptors can signal independently for granule enzyme release. Superoxide production, a measure of the respiratory burst, was obtained with increasing concentrations of IL-8 with maximum effects at 25 to 50 nM, but no response was observed upon challenge with GRO alpha or NAP-2 up to 1000 nM. The superoxide production induced by IL-8 was inhibited by anti-IL8R1, but was not affected by anti-IL8R2. Stimulation of neutrophils with IL-8, in contrast to GRO alpha or NAP-2, also elicited phospholipase D activity. The effect of IL-8 was again inhibited by anti-IL-8R1 but not by anti-IL8R2, indicating that this response, like the respiratory burst, was mediated by IL-8R1. Taken together, our results show that IL-8R1 and IL-8R2 are functionally different. Responses, such as cytosolic free Ca2+ changes and the release of granule enzymes, are mediated through both receptors, whereas the respiratory burst and the activation of phospholipase D depend exclusively on stimulation through IL-8R1.
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PMID:Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. 869 78

Several chemoattractant receptors can support agonist-induced, integrin-dependent arrest of rolling neutrophils in inflamed venules in vivo, as well as subsequent crawling into tissues. It has been hypothesized that receptors of the Galpha(i)-linked chemoattractant subfamilies, especially receptors for chemokines, may mediate parallel activation-dependent arrest of homing lymphocyte subsets. However, although several chemokines can attract subsets of B or T cells, robust chemoattractant triggering of resting lymphocyte adhesion to vascular ligands has not been observed. To study the biology of individual leukocyte chemoattractant receptors in a defined lymphoid environment, mouse L1/2 pre-B cells and/or human Jurkat T cells were transfected with alpha (IL-8 receptor A) or beta (MIP-1alpha/CC-CKR-1) chemokine receptors, or with the classical chemoattractant C5a (C5aR) or formyl peptide receptors (fPR). All receptors supported robust agonist-dependent alpha4beta1 integrin-mediated adhesion of lymphocytes to VCAM-1. L1/2 cells cotransfected with fPR and beta7 integrin were also induced to bind MAdCAM-1, suggesting common mechanisms coupling chemoattractant receptors to activation of distinct integrins. Adhesion was rapid but transient, with spontaneous reversion to unstimulated levels within 5 min after peak binding. When observed under flow conditions, alpha4beta1-mediated arrest occurred within seconds after initiation of contact and rolling of IL-8RA transfectants on VCAM-1/IL-8 co-coated surface; and arrest reversed spontaneously after a mean of 5 min with a return to rolling behavior. Each of the receptors also conferred agonist-specific chemotaxis; however, whereas strong adhesion required simultaneous occupancy of many receptors with maximal responses above the Kd, chemotaxis in each case was suppressed at high agonist concentrations. The findings indicate that alpha and beta chemokine as well as classical chemoattractant receptors can trigger robust adhesion as well as directed migration of lymphoid cells, but that the requirements for and kinetics of adhesion triggering and chemotaxis are distinct, thus permitting their independent regulation. They suggest that the discordance between proadhesive and chemoattractant responses of circulating lymphocytes to many chemokines may reflect quantitative aspects of receptor expression and/or coupling rather than qualitative differences in receptor signaling.
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PMID:Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. 869 20

In an effort to determine which regions of IL-8 are involved in interactions with its receptors, eight peptides were designed to correspond to distinct exposed regions of the IL-8 monomer, using the proton NMR-derived structure of the dimer as a basis. The peptides were evaluated singularly, and as equimolar mixtures of two to six peptides, in an IL-8 receptor binding assay and found to have no binding interaction with either alpha or beta IL-8 receptor as single peptides or mixtures of two peptides. In contrast, one of these peptides having the sequence AVLPRSAKEL, which corresponds to the N-terminal 10 amino acid residues of the 77 amino acid form of IL-8, exhibited potent chemotactic activity in human neutrophils. These results indicate that there is no contiguous ligand that can be designed based on the NMR and X-ray determined structure of IL-8 and that there may be multiple receptors responsible for neutrophil activation and chemotaxis.
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PMID:Design and evaluation of small peptides mapping the exposed surface of IL-8. 874 Sep 72

We studied the involvement of chemokines that bind to G protein-coupled receptors in the migration of skin homing T cells across a bilayer vascular construct (BVC) consisting of a fibroblast matrix underneath an activated endothelial (EC) monolayer. Based on the expression of the cutaneous lymphocyte-associated antigen (CLA), a skin homing receptor, CD45R0+ T cells freshly isolated from blood or HUT-78 cutaneous T lymphoma cells were separated into CLA+ and CLA- subpopulations. These T cells were incubated on interleukin (IL)-1 beta and tumor necrosis factor-alpha-activated EC, and the number of transmigrated cells was determined. The chemokine IL-8 was selectively involved in the enhanced migration of CLA+ T cells across activated EC as demonstrated by blocking antibody to IL-8 but not to GRO-alpha, MCP-1 and RANTES. Identical results were obtained with both human umbilical vein EC (HUVEC) and microvascular skin EC (HDMEC). Pertussis toxin selectively inhibited the enhanced transendothelial migration (TEM) of CLA+ T cells, suggesting that CLA-dependent TEM depends on Gi protein-transmitted signals. Moreover, the IL-8 receptor B (IL-8RB) appeared to be functionally involved in TEM, as demonstrated by receptor desensitization with the CXC chemokines IL-8 and GRO-alpha and by blocking the IL-8RB with specific monoclonal antibodies. Although only the IL-8RB was involved in CLA-dependent TEM, mRNA encoding IL-8RA and IL-8RB was expressed by both CLA+ and CLA- T cells. This correlated with IL-8RA and IL-8RB surface expression on these cells. Thus, the IL-8RB is selectively functional in TEM of T cells expressing the skin homing receptor CLA. Our results demonstrate a critical role for IL-8 and possibly other IL-8RB ligands in addition to the IL-8RB in TEM and suggest the involvement of these molecules in the homing of specific T cells to inflamed skin.
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PMID:The interleukin-8 receptor B and CXC chemokines can mediate transendothelial migration of human skin homing T cells. 881 46

Interleukin-8 (IL-8) exhibits activities on bone marrow progenitor cells such as regulation of their growth and their mobilization into peripheral blood. In order to clarify the molecular mechanism of the effects of IL-8 on mouse bone marrow cells, we examined the cellular distribution of mouse IL-8 receptor homologue by an immunofluorescence analysis. Peripheral blood Gr-1+ mature granulocytes, and a substantial portion of NK1.1+ natural killer cells in peripheral blood and spleen were stained positively with anti-mouse IL-8 receptor homologue antibody, whereas CD4+, CD8+, or B220+ lymphocytes in peripheral blood and spleen, and thymocytes were not. Moreover, a small portion of ER-MP20+ monocytes in peripheral blood but neither peritoneal resident nor bone marrow macrophages were stained with anti-IL-8 receptor homologue antibody. In bone marrow, mature granulocytes and to a lesser degree, metamyelocytes and myelocytes expressed IL-8 receptor homologue. Moreover, lineage marker (Lin)-c-kit+ bone marrow progenitor cells started to express IL-8 receptor homologue only 5 days after in vitro culture with IL-3 and stem cell factor when metamyelocytes and myelocytes appeared. These results indicated that myeloid lineage cells express a substantial number of IL-8 receptor homologues only at the stage of myelocytes.
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PMID:Detection of mouse IL-8 receptor homologue expression on peripheral blood leukocytes and mature myeloid lineage cells in bone marrow. 883 Jul 94

Expansion of mature neutrophils has been observed in mice lacking the murine interleukin (IL) 8 receptor homolog [mIL-8Rh(-/-)], and human (hu) IL-8 suppresses proliferation of primitive myeloid cells in vitro and in vivo. To evaluate involvement and relevance of murine IL-8 receptor homolog (mIL-8Rh) in negative regulation of myelopoiesis, we studied mIL-8Rh(-/-) and (+/+) mice raised in a normal or germ-free environment. Immature myeloid progenitors from mIL-8Rh(+/+) mice bred under normal or germ-free conditions were significantly suppressed in vitro by recombinant huIL-8, macrophage inflammatory protein (MIP)-1 alpha, platelet factor (PF) 4, interferon inducible protein (IP) 10, monocyte chemotactic peptide (MCP) 1, and H-ferritin. In contrast, progenitors from mIL-8Rh(-/-) mice were insensitive to inhibition by IL-8, but not to these other chemokines and H-ferritin. Mouse MIP-2, a ligand for mIL-8Rh, suppressed progenitors from normal but not mIL-8Rh(-/-) mice. Under normal environmental conditions, enhanced numbers of myeloid progenitors were found in femur, spleen, and blood of mIL-8Rh(-/-) compared with mIL-8Rh(+/+) mice. Numbers of myeloid progenitors were greatly decreased in mIL-8Rh(-/-)and (+/+) mice in germ-free conditions, and were either not significantly enhanced in mIL-8Rh(-/-) mice compared with (+/+) mice or were only moderately so. Differences in progenitors/organ between a germ-free and normal environment were greater for the mIL-8Rh(-/-) mice. These results document selective insensitivity of myeloid progenitor cells from mIL-8Rh(-/-) mice to inhibition by huIL-8 and mouse MIP-2 and a large expansion of myeloid progenitors in these mice, the latter effect being environmentally inducible. This provides strong support for a negative myeloid regulatory role played by the mIL-8Rh in vivo, whose active ligand may be MIP-2.
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PMID:Involvement of Interleukin (IL) 8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue. 892 Aug 70

The mechanisms by which chemokines bind and signal through their receptors are complex and poorly understood. In the present study, we sought to dissect these processes and to map important functional domains of the two CXC chemokine (interleukin-8) receptors, CXCR1 (formally IL-8RA) and CXCR2 (formally IL-8RB), using blocking monoclonal antibodies (mAbs) to the receptors and a series of chimeras between CXCR1 and CXCR2. A panel of specific mAbs against CXCR1 or CXCR2, generated by immunizing mice with transfectants expressing either receptor, were shown to effectively block IL-8- and/or growth-related oncogene alpha (GROalpha) -mediated ligand binding, chemotaxis, elastase release, and VCAM-1 binding in CXCR1 and CXCR2 transfectants and/or human neutrophils. Of particular interest was an anti-CXCR1 mAb, 7D9, that inhibited chemotaxis, elastase release, and VCAM-1 binding but had no detectable effects on ligand binding. The epitopes of these blocking mAbs were mapped by using a series of CXCR1/2 chimera transfectants and synthetic peptides. Most of the anti-CXCR1 antibodies, except 7D9, mapped to the amino acid sequence WDFDDL (CXCR1 residues 10-15), and all the anti-CXCR2 antibodies mapped to the amino acid sequence FEDFW (CXCR2 residues 6-10). The epitope of mAb 7D9 mainly involved a region within the first 45 residues of CXCR1, and it appeared to be conformation-sensitive. These results support a model in which the binding and signaling of IL-8 with its receptor occur in at least two discrete steps involving distinct domains of the receptor. This model is consistent with the notion that discrete conformational changes of the receptor secondary to ligand binding are required to trigger various biological responses. Moreover, the ligand binding and chemotaxis properties of each CXCR1/2 chimeric receptor to IL-8 and GROalpha were determined. It was found that each is distinct in its ability to confer ligand binding and chemotactic response to IL-8 and GROalpha, and two conclusions could be made. 1) The N-terminal segment of CXCR1 is a dominant determinant of receptor subtype selectivity, consistent with previous studies using rabbit/human CXCR1/2 chimeras; and 2) the specificity determinant for GROalpha binding in CXCR2 involves sequences in the N terminus, distal to the first 15 residues, as well as other parts of the receptor.
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PMID:Discrete steps in binding and signaling of interleukin-8 with its receptor. 894 Jan 21

Aberrant production of interleukin 8 (IL-8) has been shown in various human inflammatory diseases. Recent investigations in animal models using either blocking antibodies against IL-8 or disruption of the gene encoding the IL-8 receptor have revealed the involvement of IL-8 in the recruitment of neutrophils and in neutrophil-associated tissue injury in acute inflammation. These studies suggest that IL-8 is a novel target to alleviate acute inflammation. This review describes the properties of IL-8 and discusses different therapeutic approaches to target IL-8, particularly the use of humanized monoclonal antibodies against IL-8 and inhibition of IL-8 gene transcription.
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PMID:Interleukin 8 as a novel target for intervention therapy in acute inflammatory diseases. 894 14

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