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)

Previous studies from this laboratory have demonstrated that the chemokines RANTES (recombinant human regulated upon activation, normally T cell expressed and presumably secreted), macrophage chemotactic peptide-1, recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) IL-8, and IP-10 are capable of inducing human T cell infiltration into the injection site of severe combined immunodeficiency (SCID) mice reconstituted with human PBL. However, the ability of these chemokines to facilitate T cell homing into various lymphoid tissues has not been examined. Initial studies focused on the ability of rhMIP-1 beta to induce human T cell infiltration into injection sites in human PBL-SCID mice. SCID mice received s.c. injections of rhMIP-1 beta or PBS (1 microgram/injection) in the hindflank for 4 h or sequential injections for 3 days. Biopsies of the MIP-1 beta injection site revealed the presence of significant mononuclear cell accumulation 72 h after injection. Immunohistologic evaluation determined that significant numbers of human CD3+ T cells were recruited in response to MIP-1 beta injections, and this infiltration could be specifically blocked by co-administration of anti-MIP-1 beta antiserum. We subsequently examined these chemokine-injected mice for the effect of trafficking of human T cells to peripheral lymphoid organs. Flow cytometric analysis of the thymus in human PBL-SCID mice revealed that treatment with rhMIP-1 beta or rhRANTES, but not platelet factor-4, resulted in improved thymic homing of the human T cells after 72 h. This trafficking effect was shown to be direct, as pretreatment of the human T cells with the chemokines in vitro also improved peripheral lymphoid trafficking of the human cells. In addition, co-injection of rhMIP-1 beta with anti-1 beta antiserum abrogated the increase in T cell homing to the thymus. These data demonstrate that MIP-1 beta and RANTES directly augment human T cell trafficking to peripheral murine lymphoid tissues. Chemokines may, therefore, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation and homing, and may be of potential clinical use in promoting immune cell trafficking and function.
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PMID:Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice. 869 Aug 98

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

Within the gastroduodenal mucosa Helicobacter pylori infection stimulates local production of a range of proinflammatory and immunoregulatory cytokines, neutrophil infiltration, specific T- and B-cell responses and the development of gastric lymphoid follicles. Following bacterial eradication this mucosal inflammatory response resolves. Infiltrating neutrophils are likely to be one of the major mediators of mucosal damage. Neutrophil activation, including reactive oxygen metabolite production and the release of myeloperoxidase, will be induced directly by bacterial factors and indirectly through products of complement activation, bioactive lipids and host-derived cytokines. Interleukin-8, and related peptides of the chemokine family secreted by gastric epithelial cells, are likely to be important host mediators inducing neutrophil migration to sites of infection. Epithelial IL-8 is upregulated by TNF-alpha and IL-1 and directly by H. pylori strains expressing the CagA phenotype. The extent of mucosal injury may reflect bacterial density, the variability of different strains of H. pylori to induce chemokine expression in epithelial cells and the oxidative burst in neutrophils. Recent evidence from in vivo and in vitro studies shows that CagA+ VacA+ strains of H. pylori are associated with enhanced inflammatory responses and mucosal damage. Defining the specific bacterial mediators of mucosal inflammation will be important in elucidating the role of H. pylori in the pathogenesis of gastroduodenal disease.
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PMID:Gastric mucosal inflammatory responses to Helicobacter pylori. 873 Feb 57

Vascular endothelial cell addressins play an important role in lymphocyte homing in secondary lymphoid organs and in chronic inflammatory areas. A SV40 large T antigen-immortalized cell line from peripheral lymph nodes, HECa1O [Bizouarne et al., 1993a], was used to characterize the location of addressins with regard to environmental factors and cytokines. For this purpose, two monoclonal antibodies, MECA 79 and MECA 367, specific for peripheral lymph node vascular addressin and for mucosal addressin (Peyer's patches), respectively, were bound to unstimulated HECa1O cells. Both mucosal and peripheral addressins were detected inside the cells and in cellular extracts of the resting cells. On the cell surface, both addressins could be evidenced on the same cells at a moderate level of expression. They partly mediate the EL4/EL4IL2 lymphoma cells' adhesion to HECa1O cells. Supernatants of cultured peripheral lymph node or Peyers' patch cells induced expression of MECA 79 or MECA 367 antigens, respectively, on the surface of HECa1O cells. Interleukins, IL-7, IL-3, and IL-8, induced the cell-surface appearance of MECA 79 but not of MECA 367 antigen. Therefore, the same cell type synthesizes both antigens, but the expression of these antigens on the cell surface is independently regulated, thus uncovering a characteristic tissue type-specific as well as environment-sensitive properties of microvascular endothelial cells.
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PMID:Selective induction of peripheral and mucosal endothelial cell addressins with peripheral lymph nodes and Peyer's patch cell-conditioned media. 897 77

Substance P (SP) has been reported to induce inflammatory cytokine production in human neuroglial cells and peripheral lymphoid cells as well. In order to evaluate the potency of novel non-peptide antagonists of the tachykinin receptors as inhibitors of SP-induced cytokines, we used the astrocytoma cell line U373MG and blood mononuclear cells as models of central and peripheral SP-target cells, respectively. In the first part of this study, we showed that SR 140333, an NK1 tachykinin receptor antagonist, was able to inhibit strongly the SP-induced production of interleukin (IL)-6 and IL-8 in the astrocytoma cell line. The antagonistic activity of SR 140333 toward SP-induced cytokine production was specific and could not be attributed to a general anti-cytokine effect, since cytokine release induced by another inflammatory protein such as IL-1beta was not blocked by this compound. In addition, NK2 and NK3 agonist neuropeptides were at least 1000-fold less effective than SP, while SR 48968 and SR 142801 which are selective NK2 and NK3 receptor antagonists, respectively, displayed a 2.5-3 orders of magnitude lower inhibitory potency than SR 140333. All these data indicated that SR 140333 blocked SP-induced cytokine production in U373MG astrocytic cells via a specific NK1 receptor-mediated process. Since SP has also been described to trigger peripheral blood mononuclear cells (PBMNC) or monocytes to release inflammatory cytokines, we attempted, in the second part of this study, to evaluate the potential antagonistic effect of our compounds on these cells. Experiments on human PBMNC from different donors were carried out to determine first their pattern of cytokine production upon SP stimulation. Surprisingly, we noticed that SP at concentrations ranging from 0.1 to 1000 nM was unable to stimulate the release of any inflammatory cytokine tested. This raises the question of the specificity of the reported in vitro effects of SP on cytokine production by human peripheral immune cells.
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PMID:Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists. 898 72

Helicobacter pylori is the major causative agent of chronic gastritis. It is associated with duodenal and gastric ulcer and with the majority of primary gastric B-cell lymphomas; furthermore, there is a strong epidemiological association with gastric cancer. One intriguing aspect of this infection is the ability of H pylori to persist despite the vast array of host immune responses. This article reviews what is known about the immune responses against H pylori, emphasizing what is generally accepted and applicable while highlighting areas of controversy. The first section delineates the genesis of the inflammatory responses, which initiate with the production of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1, IL-6, and IL-8 and continue with the recruitment of neutrophilic polymorphonuclear cells, lymphocytes, plasma cells, macrophages and eosinophils, and later with the development and recruitment of specifically committed cells (lymphocytes sensitized to H pylori antigens and B cells producing immunoglobulin (Ig)A, IgG, and possibly IgE antibodies against a variety of H pylori surface and flagellar proteins as well as bacterial toxins). The second part of the article focuses on the development of lymphoid follicles in the gastric mucosa, a phenomenon that for the first time links an immune response (the recruitment of mucosa-associated lymphoid tissue [MALT] to the gastric mucosa in response to H pylori infection) with the development of a neoplastic growth (the development of gastric MALT lymphomas). The local and systemic antibody responses are discussed in the light of their potential application in the development of diagnostic tests and vaccines. Particular emphasis is placed on the controversies surrounding the significance of antibodies directed against a 120 to 140 kDa protein apparently associated with more "aggressive" (sometimes also called "ulcerogenic" or "pathogenic") strains of H pylori.
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PMID:The immunobiology of Helicobacter pylori gastritis. 900 Apr 97

In the mouse, mutations at the natural resistance-associated macrophage protein 1 (Nramp1) gene abrogate resistance to infection with antigenically unrelated intracellular parasites such as Mycobacterium, Salmonella, and Leishmania. Nramp1 expression is restricted to reticuloendothelial organs and peripheral blood leukocytes, where the protein may function as a membrane transporter of an as yet to be identified substrate. To identify the human blood cell type(s) expressing NRAMP1 mRNA and determine how Nramp1 expression is regulated in these cells, we have examined separated populations of peripheral blood leukocytes and in vitro cell lines. We observed that polymorphonuclear leukocytes (PMN) are the major site of NRAMP1 expression, followed to a lesser degree by monocytes (MN). Migration of MN to tissues (alveolar macrophages) or maturation in vitro (long-term culture) was associated with a higher level of NRAMP1 expression compared with blood MN. Northern analyses of RNA from model cultured cells showed absence of NRAMP1 expression in transformed cell lines from either erythroid or lymphoid T or B lineages as well as progenitors of the monocyte/macrophage pathway (KG1, U937, THP1), and the HL-60 promyelocytic leukemia. Induction of differentiation of HL-60 cells toward either the monocyte/macrophage (vitamin D3, phorbol ester) or the granulocyte pathways (DMF, DMSO), as measured by induction of IL8-Rb, c-FMS, and CD14 marker gene expression, was concomitant with a strong induction of NRAMP1 expression. These results suggest that NRAMP1 expression is specific to the myeloid lineage and is acquired during the maturation of PMN and MN. The possibility that NRAMP1 may be a component of the phagosomal/endosomal apparatus common to PMN and MN is discussed.
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PMID:Expression of the human NRAMP1 gene in professional primary phagocytes: studies in blood cells and in HL-60 promyelocytic leukemia. 900 May 42

Human tonsilla palatina and skin were investigated by means of light microscopical and electron microscopical immunohistochemistry using monoclonal antibodies (Mab) against some cytokines. In both tonsils and skin we found intracellular immunoreactivity for interleukin-1-beta in macrophages and interdigitating cells. Also some, but not all crypt-epithelial cells were positive, while keratinocytes in the skin were negative. Interleukin-2-immunoreactivity was found in a subpopulation of lymphocytes (probably T-cells) and unexpectedly also in some antigen-presenting cells (APCs). A Mab against interleukin-4 revealed weak labelling of lymphatic cells in the T-cell area of tonsils. The human skin was negative. A Mab that recognizes a molecule associated with the interleukin-4-receptor gave strong surface labelling in tonsils and skin on APCs and weak immunoreactivity on lymphoid cells. Frequently these APCs formed rosettes with weakly labeled lymphocytes. Mabs against interleukin-8 stained starry sky macrophages in the germinal centers of the tonsil and different APCs in the T-cell region. IL-8 is stored in keratinocytes of normal skin, but becomes mobilized under inflammatory conditions. Our results expand the understanding of cell cell-interactions under normal and inflammatory conditions in tonsil and skin.
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PMID:Immunohistochemical localization of cytokines and receptor-associated molecules in human tonsils and skin. 908 14

During the past decade our knowledge of the cellular and molecular events associated with key immunological responses has been greatly advanced by the use of isolated subpopulations of immunocompetent cells, cloned cell lines and recombinant derived cytokines. Valuable as these studies have been they do not truly reflect the complex integrative events which take place in both primary and secondary lymphoid tissue both in vivo and in vitro. In order to address this problem we have developed a tissue culture procedure which is a modification of that previously used by others to study T cell maturation in the thymus. This involves culturing precision cut slices of human lymphoid tissue in a sponge culture system. Using this technique we have observed marked differences in both immunoglobulin and cytokine secretion between slices and suspensions of human spleen. In brief, cultured slices (mitogen stimulated or otherwise) consistently secrete higher levels of immunoglobulin, IL-1 beta, IL-6, IL-8 and IL-11 and exhibit much lower proliferation than suspensions of the same tissue. Mitogen stimulated suspensions on the other hand secrete higher levels of IL-2, IL-4, IL-10 and TNF alpha than do slices. These differences are also observed at the intracellular cytokine level. Additional studies reveal that the immunoglobulin and cytokine secretion observed is largely due to the de novo synthesis of these molecules and not as a result of spontaneous secretion of preformed products. Furthermore immunoglobulin secretion in both slices and suspensions can be inhibited by the addition of specific antibodies to IL-1 beta, IL-6 and TNF alpha while IL-6 production can be differentially modulated by a variety of substances. Preliminary studies indicate that close interaction between B cells and stromal cells within explants accounts for some of the observed differences. This review article describes the basic technique, summarises the results we have obtained in this system and outlines the possible basis of the observed differences.
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PMID:A comparison of the performance in vitro of precision cut tissue slices and suspensions of human spleen with special reference to immunoglobulin and cytokine production. 914 Jul 25

CAAT/enhancer binding proteins (C/EBP) are a family of transcription factors that mediates adipocyte differentiation and the regulation of genes expressed in immune responses and inflammation, such as interleukin-6 (IL-6), IL-8, and granulocyte colony-stimulating factor (G-CSF). We investigated the role of C/EBPbeta (NF-IL6) in the generation of bone marrow B lymphocytes by taking advantage of C/EBPbeta-/- mice. We found that the expansion of bone marrow (BM) B lymphocytes was impaired in long-term lymphoid cultures from C/EBPbeta-/- mice. Consistent with this finding, the number of BM B cells was decreased in C/EBPbeta-/- mice. Both the levels of IL-7 gene expression and bioactive IL-7 from BM stromal cells were decreased in C/EBPbeta-/- mice. Furthermore, the proliferative responsiveness of BM B-cell precursors to IL-7 was also reduced as compared to wild-type mice, indicating that C/EBPbeta is required for the generation of BM B cells induced by IL-7. Accordingly, IL-7 stimulates the C/EBPbeta DNA-binding activity of normal BM pre-B lymphocytes as well as of 70Z/3 pre-B cells. These results point to C/EBPbeta as a critical signaling molecule in BM B lymphopoiesis.
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PMID:Impaired generation of bone marrow B lymphocytes in mice deficient in C/EBPbeta. 920 49


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