Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.
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PMID:Determinants of human B cell migration across brain endothelial cells. 1270 26

Toll-like receptors (TLRs) are pattern recognition receptors that serve an important function in detecting pathogens and initiating inflammatory responses. Upon encounter with foreign Ag, dendritic cells (DCs) go through a maturation process characterized by an increase in surface expression of MHC class II and costimulatory molecules, which leads to initiation of an effective immune response in naive T cells. The innate immune response to bacterial flagellin is mediated by TLR5, which is expressed on human DCs. Therefore, we sought to investigate whether flagellin could induce DC maturation. Immature DCs were cultured in the absence or presence of flagellin and monitored for expression of cell surface maturation markers. Stimulation with flagellin induced increased surface expression of CD83, CD80, CD86, MHC class II, and the lymph node-homing chemokine receptor CCR7. Flagellin stimulated the expression of chemokines active on neutrophils (IL-8/CXC chemokine ligand (CXCL)8, GRO-alpha/CXCL1, GRO-beta/CXCL2, GRO-gamma/CXCL3), monocytes (monocyte chemoattractant protein-1/CC chemokine ligand (CCL)2), and immature DCs (macrophage-inflammatory protein-1 alpha/CCL3, macrophage-inflammatory protein-1 beta/CCL4), but not chemokines active on effector T cells (IFN-inducible protein-10 kDa/CXCL10, monokine induced by IFN-gamma/CXCL9, IFN-inducible T cell alpha chemoattractant/CXCL11). However, stimulating DCs with both flagellin and IFN-inducible protein-10 kDa, monokine induced by IFN-gamma, and IFN-inducible T cell alpha chemoattractant expression, whereas stimulation with IFN-beta or flagellin alone failed to induce these chemokines. In functional assays, flagellin-matured DCs displayed enhanced T cell stimulatory activity with a concomitant decrease in endocytic activity. Finally, DCs isolated from mouse spleens or bone marrows were shown to not express TLR5 and were not responsive to flagellin stimulation. These results demonstrate that flagellin can directly stimulate human but not murine DC maturation, providing an additional mechanism by which motile bacteria can initiate an acquired immune response.
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PMID:The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. 1273 64

Neutrophil responses to commercial LPS, a dual Toll-like receptor (TLR)2 and TLR4 activator, are regulated by TLR expression, but are amplified by contaminating monocytes in routine cell preparations. Therefore, we investigated the individual roles of TLR2 and TLR4 in highly purified, monocyte-depleted neutrophil preparations, using selective ligands (TLR2, Pam(3)CysSerLys(4) and Staphylococcus aureus peptidoglycan; TLR4, purified LPS). Activation of either TLR2 or TLR4 caused changes in adhesion molecule expression, respiratory burst (alone, and synergistically with fMLP), and IL-8 generation, which was, in part, dependent upon p38 mitogen-activated protein kinase signaling. Neutrophils also responded to Pam(3)CysSerLys(4) and purified LPS with down-regulation of the chemokine receptor CXCR2 and, to a lesser extent, down-regulation of CXCR1. TLR4 was the principal regulator of neutrophil survival, and TLR2 signals showed relatively less efficacy in preventing constitutive apoptosis over short time courses. TLR4-mediated neutrophil survival depended upon signaling via NF-kappa B and mitogen-activated protein kinase cascades. Prolonged neutrophil survival required both TLR4 activation and the presence of monocytes. TLR4 activation of monocytes was associated with the release of neutrophil survival factors, which was not evident with TLR2 activation, and TLR2 activation in monocyte/neutrophil cocultures did not prevent late neutrophil apoptosis. Thus, TLRs are important regulators of neutrophil activation and survival, with distinct and separate roles for TLR2 and TLR4 in neutrophil responses. TLR4 signaling presents itself as a pharmacological target that may allow therapeutic modulation of neutrophil survival by direct and indirect mechanisms at sites of inflammation.
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PMID:Selective roles for Toll-like receptor (TLR)2 and TLR4 in the regulation of neutrophil activation and life span. 1273 76

There is increasing evidence that both cell adhesion molecules and soluble factors are involved in tumor metastasis. We have found that endothelial cells secrete chemoattractants that can induce melanoma cell chemotaxis. Protein separation on an ion-exchange column shows the association of IL-8 with fractions that contain the chemoattractant activity. This activity is completely lost from the conditioned medium after immunoprecipitation with anti-IL-8 antibodies, indicating that IL-8 is the major melanoma chemoattractant secreted by endothelial cells. IL-877, the predominant endothelial IL-8 isoform that contains 77 amino acids, is found to be twice as potent as the more common 72-amino acid isoform IL-872. Antibody inhibition studies indicate that the chemotactic response of melanoma cells is mediated by the CXC-chemokine receptor CXCR1 and not by the more promiscuous CXCR2. When stimulated by tumor necrosis factor alpha, the nonresponsive WM35 melanoma cells synthesize a higher level of CXCR1 and become chemotactic toward interleukin (IL)-8. Pretreatment of cells with pertussis toxin nullifies their chemotactic response, suggesting the involvement of G proteins. Antibodies against either IL-8 or CXCR1 inhibit melanoma transendothelial migration in a coculture assay by 30%. These results are consistent with a role for IL-8-induced chemotaxis in the transendothelial migration of melanoma cells.
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PMID:Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. 1273 12

Viruses encode proteins that disrupt chemokine responses. The murine gammaherpesvirus 68 gene M3 encodes a chemokine binding protein (vCKBP-3) which has no sequence similarity to chemokine receptors but inhibits chemokine receptor binding and activity. We have used a panel of CXCL8 analogs to identify the structural requirements for CXCL8 to bind to vCKBP-3 in a scintillation proximity assay. Our data suggest that vCKBP-3 acts by mimicking the binding of chemokine receptors to CXCL8.
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PMID:The gammaherpesvirus chemokine binding protein binds to the N terminus of CXCL8. 1285 30

Homo- and hetero-oligomerization have been reported for several G protein-coupled receptors (GPCRs). The CXCR2 is a GPCR that is activated, among the others, by the chemokines CXCL8 (interleukin-8) and CXCL2 (growth-related gene product beta) to induce cell chemotaxis. We have investigated the oligomerization of CXCR2 receptors expressed in human embryonic kidney cells and generated a series of truncated mutants to determine whether they could negatively regulate the wild-type (wt) receptor functions. CXCR2 receptor oligomerization was also studied by coimmunoprecipitation of green fluorescent protein- and V5-tagged CXCR2. Truncated CXCR2 receptors retained their ability to form oligomers only if the region between the amino acids Ala-106 and Lys-163 was present. In contrast, all of the deletion mutants analyzed were able to form heterodimers with the wt CXCR2 receptor, albeit with different efficiency, competing for wt/wt dimer formation. The truncated CXCR2 mutants were not functional and, when coexpressed with wt CXCR2, interfered with receptor functions, impairing cell signaling and chemotaxis. When CXCR2 was expressed with the AMPA-type glutamate receptor GluR1, CXCR2 dimerization was again impaired in a dose-dependent way, and receptor functions were prejudiced. In contrast, CXCR1, a chemokine receptor that shares many similarities with CXCR2, did not dimerize alone or with CXCR2 and when coexpressed with CXCR2 did not impair receptor signaling and chemotaxis. The formation of CXCR2 dimers was also confirmed in cerebellar neuron cells. Taken together, we conclude from these studies that CXCR2 functions as a dimer and that truncated receptors negatively modulate receptor activities competing for the formation of wt/wt dimers.
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PMID:Ligand-independent CXCR2 dimerization. 1288 58

Evasion of host immune responses is well documented for viruses and may also occur during tumor immunosurveillance. The mechanisms involve alterations in MHC class I expression, Ag processing and presentation, chemokine and cytokine production, and lymphocyte receptor expression. Epithelial tumors overexpress MHC class I chain-related (MIC) molecules, which are ligands for the activating receptor NKG2D on NK and T cells. We report that NK cells from patients with colorectal cancer lack expression of activating NKG2D and chemokine CXCR1 receptors, both of which are internalized. Serum levels of soluble MIC (sMIC) are elevated and are responsible for down-modulation of NKG2D and CXCR1. In contrast, high serum levels of CXC ligands, IL-8, and epithelial-neutrophil-activating peptide (ENA-78) do not down-modulate CXCR1. In vitro, internalization of NKG2D and CXCR1 occurs within 4 and 24 h, respectively, of incubating normal NK cells with sMIC-containing serum. Furthermore, natural cytotoxicity receptor NKp44 and chemokine receptor CCR7 are also down-modulated in IL-2-activated NK cells cocultured in MIC-containing serum-an effect secondary to the down-modulation of NKG2D and not directly caused by physical association with sMIC. The patients' NK cells up-regulate expression of NKG2D, NKp44, CXCR1, and CCR7 when cultured in normal serum or anti-MIC Ab-treated autologous serum. NKG2D(+) but not NKG2D(-) NK cells are tumoricidal in vitro, and in vivo they selectively traffic to the xenografted carcinoma, form immunological synapse with tumor cells, and significantly retard tumor growth in the SCID mice. These results suggest that circulating sMIC in the cancer patients deactivates NK immunity by down-modulating important activating and chemokine receptors.
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PMID:Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. 1466 96

Chemokine receptors play an important role in the migration of leukocytes to sites of allergic inflammation in humans. In this study, we have identified increased expression of the chemokine receptor CXCR1 on CD4+ T lymphocytes derived from patients with atopic disease compared with normal donors. Enhanced expression of CXCR1 by atopic donors was identified on freshly isolated peripheral blood cells and on expanded cell populations derived from nasal mucosal biopsies and from the periphery. Identification of CXCR1 expression on CD4 cells in the nasal mucosa was confirmed by double immunofluorescence. In addition, expression of CXCR1 was dramatically decreased in patients undergoing successful treatment of allergic rhinitis by specific immunotherapy. CXCR1 provided a functional receptor capable of regulating T cells in the context of allergic disease, since expression of CXC chemokine ligand 8 was up-regulated at the site of allergic inflammation and freshly isolated CXCR1+CD4+ cells from atopic donors showed an enhanced functional response to this ligand. CXCR1 expression on CD4+ T cells was increased in vitro in response to the pro-Th2 cytokine IL-4. Phenotypic analysis reveals that IFN-gamma expression was lower in the CXCR1+CD4+ cells. The identification of CXCR1 as a marker of allergic rhinitis reveals a possible target for therapeutic intervention in atopic disease.
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PMID:CXCR1+CD4+ T cells in human allergic disease. 1468 34

The acquisition of a metastatic phenotype in breast epithelial cells is a progressive process, influenced by a large variety of cellular and soluble factors. Of these, members of the chemokine superfamily, such as CCL2, CCL5, CXCL8 and CXCL12 have been recently suggested to promote breast cancer progression. A pre-requisite for elucidation of the role of other chemokines in breast cancer progression is the characterization of chemokine and chemokine receptor expression by breast tumor cells. The present study focuses on CXCL10, a CXC chemokine that was recently suggested to have anti-malignant properties, and its corresponding receptor CXCR3. CXCR3 expression was detected in three human breast adenocarcinoma cell lines, MDA-MB-231, MCF-7 and T47D. CXCR3 expression was potently up-regulated by growing the cells under stress conditions, imposed by serum starvation. Unlike many other chemokine receptors, CXCR3 expression was not down-regulated by exposure to high concentrations (500ng/ml) of its ligand, CXCL10, but rather was promoted. CXCL10-induced up-regulation of CXCR3 expression in the three cell lines was inhibited by cycloheximide, indicating that de novo protein synthesis is required for this process. In addition to CXCR3, the secretion of CXCL10 was noted in the MDA-MB-231, MCF-7 and T47D cells. CXCL10 secretion was found to be down-regulated by IL-6, a potentially pro-malignant cytokine in breast cancer. The concomitant expression of CXCR3 and CXCL10 in breast tumor cells suggests that a CXCR3-CXCL10 axis may function in these cells, and paves the way for an in depth analysis of CXCL10-CXCR3 interactions in breast tumor cells.
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PMID:The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines. 1508 42

Eosinophil-mediated diseases, such as allergic asthma, eosinophilic fasciitis, and certain hypersensitivity pulmonary disorders, are characterized by eosinophil infiltration and tissue injury. Mast cells and T cells often colocalize to these areas. Recent data suggest that mast cells can contribute to eosinophil-mediated inflammatory responses. Activation of mast cells can occur by antigen and immunoglobulin E (IgE) via the high-affinity receptor (FcepsilonRI) for IgE. The liberation of proteases, leukotrienes, lipid mediators, and histamine can contribute to tissue inflammation and allow recruitment of eosinophils to tissue. In addition, the synthesis and expression of a plethora of cytokines and chemokines (such as granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-1 [IL-1], IL-3, IL-5, tumor necrosis factor-alpha [TNF-alpha], and the chemokines IL-8, regulated upon activation normal T cell expressed and secreted [RANTES], monocyte chemotactic protein-1 [MCP-1], and eotaxin) by mast cells can influence eosinophil biology. Stem cell factor (SCF)-c-kit, cytokine-cytokine receptor, and chemokine-chemokine receptor (CCR3) interactions leading to nuclear factor kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK) expression, and other signaling pathways can modulate eosinophil function. Eosinophil hematopoiesis, activation, survival, and elaboration of mediators can all be regulated thus by mast cells in tissue. Moreover, because eosinophils can secrete SCF, eosinophils can regulate mast cell function in a paracrine manner. This two-way interaction between eosinophils and mast cells can pave the way for chronic inflammatory responses in a variety of human diseases. This review summarizes this pivotal interaction between human mast cells and eosinophils.
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PMID:The role of human mast cell-derived cytokines in eosinophil biology. 1515 10


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