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)

Astrocytes are a major cellular component of the brain that are capable of intense proliferation and metabolic activity during diverse inflammatory brain diseases (such as multiple sclerosis, Alzheimer's dementia, tumor, HIV encephalitis, or prion disease). In this biological process, called reactive gliosis, astrocyte apoptosis is frequently observed and could be an important mechanism of regulation. However, the factors responsible for apoptosis in human astrocytes are poorly defined. Here, we report that short term cultured astrocytes derived from different brain regions express significant levels of CD95 at their surface. Only late passage astrocytes are sensitive to CD95 ligation using either CD95 mAb or recombinant CD95 ligand. Blocking experiments using caspase inhibitors with different specificities (DEVD-CHO, z-VAD-fmk, and YVAD-cmk), an enzymatic activity assay, and immunoblotting show that CPP32/caspase-3 play a prominent role in CD95-induced astrocyte death. In contrast, early passage astrocytes are totally resistant to death, but a significant increase in astrocytic IL-8 secretion (p < 0.001, by Wilcoxon's test for paired samples) is observed after CD95 triggering. Production of IL-8 contributes to the resistance of astrocytes to CD95 ligation. Furthermore, in the presence of IFN-gamma, resistant astrocytes became sensitive to CD95-mediated death. These data suggest that microenvironmental factors can influence the consequences of CD95 ligation on astrocytes. Therefore, we propose that CD95 expressed by human astrocytes plays a pivotal role in the regulation of astrocyte life and death and may be a key factor in inflammatory processes in the brain, such as reactive gliosis.
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PMID:CD95 (Fas/Apo-1) as a receptor governing astrocyte apoptotic or inflammatory responses: a key role in brain inflammation? 997 11

TWEAK is a recently described member of the Tumor Necrosis Factor (TNF) ligand family whose transcripts are present in a wide variety of human tissues (Chicheportiche, Y., Bourdon, P. R., Xu, H., Hsu Y. M., Scott, H., Hession, C., Garcia, I., and Browning, J. L. (1997) J. Biol. Chem. 272, 32401-32410). TWEAK is a weak inducer of apoptosis in transformed cells when administered with interferon-gamma or cycloheximide (Chicheportiche, Y., Bourdon, P. R., Xu, H., Hsu Y. M., Scott, H., Hession, C., Garcia, I., and Browning, J. L. (1997) J. Biol. Chem. 272, 32401-32410; Masters, S. A., Sheridan, J. P., Pitti, R. M., Brush, A. G., and Ashkenazi, A. (1998) Curr. Biol. 8, 525-528) and also promotes IL-8 secretion in cultured cells. We report here that picomolar concentrations of recombinant soluble TWEAK induce proliferation in a variety of normal human endothelial cells and in aortic smooth muscle cells and reduce culture requirements for serum and growth factors. Blocking antibodies to Vascular Endothelial Growth Factor (VEGF) do not significantly inhibit TWEAK-induced proliferation, indicating that TWEAK does not function indirectly through up-regulation of VEGF. Pellets containing TWEAK induce a strong angiogenic response when implanted in rat corneas, suggesting a role for TWEAK in vasculature formation in vivo.
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PMID:TWEAK induces angiogenesis and proliferation of endothelial cells. 1008 77

Polymorphonuclear leukocytes (PMN) and eosinophils (Eos) are important cellular participants in a variety of acute and chronic inflammatory reactions in the airway. Histologic evidence has implicated direct interactions between these two subsets of leukocytes and airway epithelial cells during inflammation. A comprehensive characterization and comparison of physiologic stimuli and adhesion molecule involvement in granulocyte-epithelial-cell interactions done with nontransformed human airway epithelial cells has not been reported. We therefore examined the regulation and biochemical mechanisms governing granulocyte-epithelial-cell adhesion, using either purified PMN or Eos and primary cultures of human bronchial epithelial cells (HBECs). We investigated the involvement of a number of proinflammatory signals associated with allergic and nonallergic airway inflammation, as well as the contribution of several epithelial and leukocyte adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and members of the beta(1), beta(2), and beta(7) integrin families. ICAM-1 was expressed at low levels on cultured HBECs and was markedly upregulated after stimulation with interferon (IFN)-gamma or, to a lesser extent, with tumor necrosis factor (TNF)-alpha or interleukin (IL)-1. VCAM-1 was not present on resting HBECs, and was not upregulated after stimulation with IFN-gamma, IL-1, IL-4, or TNF-alpha. PMN adhesion to HBECs could be induced either through activation of PMN with IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), or C5a, but not with IL-5 or by preactivation of HBECs with TNF-alpha or IFN-gamma. Blocking antibody studies indicated that PMN-HBEC adherence depended on beta(2) integrins, primarily alpha(M)beta(2) (Mac-1). Adherence of Eos to HBECs could be induced through activation of Eos with IL-5, GM-CSF, or C5a, but not with IL-8 or by prior activation of HBECs with TNF-alpha of IFN-gamma. Maximal adhesion of Eos and PMN required pretreatment of HBECs with either TNF-alpha or IFN-gamma in addition to leukocyte activation. Adherence of Eos to unstimulated HBECs was mediated through both beta(1) and beta(2) integrins, whereas adhesion of Eos to activated HBECs was dominated by beta(2) integrins. Adhesion of both Eos and PMN was inhibited by treatment of HBECs with blocking antibodies to ICAM-1. Differential utilization of beta(1) and beta(2) integrins by Eos, depending on the activation state of the epithelium, is a novel finding and may affect activation and/or recruitment of Eos in airway tissue. Mechanisms of adhesion of HBECs to Eos and PMN, as evidenced by the different responsiveness of the two latter types of cells to IL-8 and IL-5, may account for a prevalence of Eos over PMN in certain airway diseases.
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PMID:Mechanisms and regulation of polymorphonuclear leukocyte and eosinophil adherence to human airway epithelial cells. 1046 Jul 60

Blocking chemokine production or action is a major target for pharmacological intervention in different human diseases. Bindarit (2-methyl-2-[[1-(phenylmethyl)-1H-indazol-3yl]methoxy]propan oic acid) dose-dependently inhibited MCP-1 and TNF-alpha production induced in vitro in monocytes by LPS and Candida albicans. It did not affect the production of the cytokines IL-1, IL-6, or the chemokines IL-8, MIP-1alpha and RANTES. In the air pouch model in mice, oral treatment reduced monocyte recruitment and local MCP-1 production, induced by carrageenan or IL-1 injection. In NZB/W mice, a model of lupus nephritis, oral treatment prolonged survival and delayed the onset of proteinuria. The results presented here show that bindarit is a preferential inhibitor of the production of MCP-1 in vitro and in vivo and suggest that its beneficial effects in models of joint and kidney inflammation are related to its anti-MCP-1 action. It is therefore possible to selectively and differentially regulate chemokines by targeting their production with small synthetic molecules.
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PMID:A small synthetic molecule capable of preferentially inhibiting the production of the CC chemokine monocyte chemotactic protein-1. 1047 1

Malignant lymphocyte migration into and within lymphoreticular tissue is an important aspect of chronic lymphocytic leukemia (CLL), yet little is known about the processes involved. Our previous studies of integrin expression and function in CLL have shown that the abnormal cells are relatively nonadhesive and nonmotile on the protein ligands of these receptors. Here we show that CLL cells adhere to a non-protein ligand, hyaluronan (HA), and become motile (as assessed by both Boyden chamber migration and time-lapse video microscopy) on this ligand when stimulated with interleukin (IL) 8. The combined presence of HA and IL-8 was essential for this motility because IL-8 did not stimulate movement on other surfaces. Blocking antibodies showed that this motility is mediated by the receptor for HA-mediated motility (RHAMM), without the involvement of CD44. Moreover, confocal microscopy showed a polarized distribution of RHAMM and F-actin, but not CD44, in cells which had become motile on HA in the presence of IL-8. Immunohistochemical studies of nodes and spleen demonstrated an abundant reticular network of HA-containing fibers throughout diseased nodes and in splenic white pulp. The splenic red pulp and the luminal surface of high endothelial venules lacked HA. IL-8 was ubiquitously present in these tissues. CLL cells were shown to move spontaneously on fibroblast monolayers derived from lymphoid tissue; this movement was largely blocked by hyaluronidase or anti-RHAMM or anti-IL-8 antibodies. These studies indicate that IL-8-induced motility on HA is likely to be important for CLL cell migration through lymphoid tissue.
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PMID:The role of hyaluronan and interleukin 8 in the migration of chronic lymphocytic leukemia cells within lymphoreticular tissues. 1048 92

The purpose of this study was to investigate the role and regulation of the CXC chemokine GRO and the interaction between GRO and IL-8 in LPS-induced uveitis in rabbits. Uveitis was induced by intravitreal injection of 100 ng of LPS in rabbits. After the LPS injection, GRO was produced in aqueous humor and peaked at 24 hr. Immunohistochemistry showed that ciliary epithelial cells were responsible for production of GRO. Blocking the activity of GRO by anti-GRO serum reduced LPS-induced aqueous neutrophil counts by 80%, but did not reduce the mononuclear cell counts or protein levels or IL-8 levels. Regulation of GRO production by TNFalpha, IL-1 and IL-8 was studied. Anti-TNFalphamAb alone did not inhibit the 24 hr LPS induced GRO levels, whereas rrIL-1Ra inhibited the GRO production by 58%. The combination of anti-TNFalpha mAb and rrIL-1Ra inhibited 93% of GRO production. Although treatment with anti-IL-8 IgG inhibited the neutrophil infiltration by 66%, treatment with this antibody did not inhibit GRO production. Taken together, our results suggest that GRO is an essential mediator for neutrophil infiltration in LPS-induced uveitis in rabbits. Most of GRO production is mediated by TNFalpha and IL-1. GRO and IL-8 act in concert to mediate neutrophil infiltration.
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PMID:CXC chemokine GRO is essential for neutrophil infiltration in LPS-induced uveitis in rabbits. 1065 48

Various bacterial cell wall components have been shown to induce hyporesponsiveness in macrophages (MAC). Here, mycobacterial glycolipids were employed to determine whether they induce a state of 'tolerance/hyporesponsiveness' in MAC in vitro in order to assess whether mycobacterial components negatively affect the immune response to Mycobacterium tuberculosis. Arabinosylated lipoarabinomannan (ARA-LAM) stimulated hyporesponsiveness by reducing TNF-alpha, GM-CSF, G-CSF, IL-10, and IL-6 release similarly to LPS, but caused no changes in IL-8 secretion. Mannose-capped LAM (MAN-LAM) acted in a different way in that TNF-alpha, GM-CSF, and IL-10 were upregulated after restimulation of MAC. Blocking experiments by mannan suggest mannose-receptor involvement in MAN-LAM activation only. Cross-stimulation experiments demonstrated a hierarchy of signaling, with LPS being the most potent stimulator and mediating abrogation of ARA-LAM-stimulated tolerance but not vice versa. MAN-LAM was the least potent stimulator of either MAC activation and induction of hyporesponsiveness. Similarly to LPS, ARA-LAM upregulated CD14 surface expression after restimulation. Recurrent MAN-LAM treatment either downmodulated or did not induce any change in CD14 expression. The role of MAN-LAM regulated cytokine secretion as well as implications regarding M. tuberculosis infection will be discussed.
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PMID:Differential tolerance induction by lipoarabinomannan and lipopolysaccharide in human macrophages. 1086 91

Stem cell trafficking between extravascular marrow sites and circulating blood is an essential part of the blood stem cell transplantation technology. Recombinant human G-CSF (rHuG-CSF) is widely used for stem cell peripheralization alone or together with chemopriming mobilizing early and pluripotent CD34+ cell subsets. New cytokine/chemokine mobilization regimens are under investigation such as combined rHuG-CSF and rHu thrombopoietin, rHuG-CSF and interleukin 3, rHuG-CSF and rHu stem cell factor, rHuG-CSF and Flt-3 ligand, human macrophage inflammatory protein, interleukin 1, and interleukin 8. Modifying the adherence of CD34+ cells to extracellular matrix molecules is a new mechanism by which hematopoietic progenitor cells are released into the circulating blood. Blocking the alpha4beta1 integrin receptor on CD34+ progenitor cells by using monoclonal antibodies specific for the heterodimeric complex alpha4beta1 has been shown to further increase the circulating stem cell concentration when given following rHuG-CSF priming. The current clinical research is primarily focused on improving stem cell mobilization efficiency in heavily pretreated and poorly mobilizing patients, and to decrease adverse effects of cytokine treatment.
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PMID:In vivo expansion of the circulating stem cell pool. 1101 55

To investigate human basophil responses to chemokines, we have developed a sensitive assay that uses flow cytometry to measure leukocyte shape change as a marker of cell responsiveness. PBMC were isolated from the blood of volunteers. Basophils were identified as a single population of cells that stained positive for IL-3Ralpha (CDw123) and negative for HLA-DR, and their increase in forward scatter (as a result of cell shape change) in response to chemokines was measured. Shape change responses of basophils to chemokines were highly reproducible, with a rank order of potency: monocyte chemoattractant protein (MCP) 4 (peak at <1 nM) >/= eotaxin-2 = eotaxin-3 >/= eotaxin > MCP-1 = MCP-3 > macrophage-inflammatory protein-1alpha > RANTES = MCP-2 = IL-8. The CCR4-selective ligand macrophage-derived chemokine did not elicit a response at concentrations up to 10 nM. Blocking mAbs to CCR2 and CCR3 demonstrated that responses to higher concentrations (>10 nM) of MCP-1 were mediated by CCR3 rather than CCR2, whereas MCP-4 exhibited a biphasic response consistent with sequential activation of CCR3 at lower concentrations and CCR2 at 10 nM MCP-4 and above. In contrast, responses to MCP-3 were blocked only in the presence of both mAbs, but not after pretreatment with either anti-CCR2 or anti-CCR3 mAb alone. These patterns of receptor usage were different from those seen for eosinophils and monocytes. We suggest that cooperation between CCRs might be a mechanism for preferential recruitment of basophils, as occurs in tissue hypersensitivity responses in vivo.
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PMID:Basophil responses to chemokines are regulated by both sequential and cooperative receptor signaling. 1112 Aug 55

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men in which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow. Fibroblast growth factor (FGF) 2, a potent growth factor for prostatic stromal and epithelial cells, is increased twofold in BPH and its concentration is correlated with stromal proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF2-expressing stromal cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF2 expression by stromal cells. Conditioned medium from primary cultures of prostatic epithelial cells was capable of inducing increased expression of FGF2 by primary stromal cultures. Blocking experiments with neutralizing anti-interleukin (IL)-8 antibodies and pretreatment with lipopolysaccharide, which down-regulates the IL-8 receptor, show that this inducing activity is because of the presence of IL-8 in the epithelial-conditioned medium. Analysis of normal prostatic peripheral zone and BPH tissue by enzyme-linked immunosorbent assay reveals that IL-8 is present at increased levels in hyperplastic prostate. Therefore IL-8 produced by prostatic epithelial cells can induce FGF2, a potent stromal and epithelial growth factor, and in this manner promote the abnormal proliferation of the prostatic transition zone that is critical in the pathogenesis of BPH.
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PMID:Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia. 1143 62

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