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)

Research into the cause and pathophysiological mechanisms underlying expression of psoriatric skin lesions has been hampered by lack of an appropriate animal model for this common and enigmatic cutaneous disease. These studies characterize normal skin, pre-psoriatic skin, and psoriatic plaque skin samples transplanted onto severe combined immunodeficiency mice. In this report we document that 1), normal, prepsoriatic, and psoriatic plaque keratome skin samples can be transplanted onto severe combined immunodeficiency mice reliably with high rates of graft survival (> 85%) and with reproducible changes consistently observed over prolonged periods of engraftment; 2), after transplantation, by clinical assessment and routine light microscopy, normal skin remained essentially normal whereas pre-psoriatic skin became thicker, and psoriatic plaque skin retained its characteristic plaque-type elevation and scale; 3), by using a panel of antibodies and immunohistochemical analysis, the overall phenotype of human cell types (including immunocytes) that persisted in the transplanted skin was remarkably similar to the immunophenotype of pretransplanted skin samples; 4), clearly recognized interface zones between human and murine skin within the epidermal and dermal compartments could be identified by routine microscopy and immunostaining, with focal areas of chimerism; and 5), elevated interleukin 8 cytokine levels were present in transplanted pre-psoriatic and psoriatic plaque skin samples. We conclude that there are many similarities between pre- and post-transplanted human samples of normal and psoriatic skin that are grafted onto severe combined immunodeficiency mice. Thus, we propose that this new animal model is appropriate for additional mechanistic-type studies designed to reveal the underlying genetic/etiological abnormality, as well as better illuminate the pathophysiological basis, for this important skin disease.
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PMID:Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. 788 40

The Burkitt's lymphoma receptor 1 (BLR1) identified initially in Burkitt lymphoma cells has been the first member of the superfamily of G-protein-coupled receptors with a lymphocyte specific expression pattern. BLR1 shows significant relationship to receptors for chemokines (IL-8, MIP-1 beta) and neuropeptides. The gene encoding the murine homologue of the human BLR1 receptor was isolated and used to study its tissue-specific expression. Blr-1 consists of two exons encoding a protein of 374 amino acid residues which shows 83% identity with the human homologue. Screening of normal tissues of adult BALB/c mice revealed that blr-1-specific RNA is detected consistently at low levels in secondary lymphatic organs. The blr-1 gene is expressed regularly and strongly in lymphomas of mature B cells but not in plasmacytomas. SCID mice deficient in the development of mature B cells have strongly reduced levels of blr-1-specific RNA in the spleen. Cytokine mediated induction (IL4, IL6) of terminal differentiation of resting B cells towards Ig-secreting plasma cells completely downregulates expression of blr-1. RNA in situ hybridization using brain sections demonstrates blr 1 transcription in the granule and Purkinje cell layer of the cerebellum. The precise delineation of the restricted expression pattern of the blr-1 gene will support the identification of its ligand and may provide a clue to understand how BLR1 exerts its biological function within the immune and nervous system.
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PMID:Selective expression of the murine homologue of the G-protein-coupled receptor BLR1 in B cell differentiation, B cell neoplasia and defined areas of the cerebellum. 792 Jan 82

The BLR1 gene, isolated initially from Burkitt's lymphoma cells (Eur. J. Immunol. 1992. 22: 2795), encodes a G protein-coupled receptor with significant relationship to receptors for chemokines (IL-8, MIP-1 alpha) and neuropeptides. The murine homologue of human BLR1 was cloned and used to investigate its expression in vivo. blr1-specific transcripts are observed in secondary lymphatic organs and to a lesser extent in brain of adult mice but not in other tissues. RNA in situ hybridization localizes blr1 transcription to primary follicles and to the mantle zone of secondary follicles. SCID mice in which mature B cell development is severely impaired exhibit a strongly reduced level of blr1-specific RNA in the spleen. The analysis of murine lymphoid tumor cell lines representing distinct stages of the B cell lineage reveals elevated expression of blr1 in B cell lymphomas but not in pre-B lymphomas or plasmacytomas. Induction of differentiation of resting B cells by cytokines or mitogens down-regulates expression of blr1. RNA in situ hybridization using brain sections of adult mice detects blr1 transcription in the granule and Purkinje cell layer of the cerebellum. Interestingly, the blr1 gene is also expressed during late embryogenesis in fetal liver and brain. In view of the remarkable expression pattern in the B cell lineage we suggest that murine BLR1 may represent a cytokine/neuropeptide receptor exerting regulatory functions on recirculating mature B lymphocytes.
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PMID:The G protein-coupled receptor BLR1 is involved in murine B cell differentiation and is also expressed in neuronal tissues. 840 54

Bacterial superantigens are the most potent known activators of human T lymphocytes. To engineer superantigens for immunotherapy of human colon carcinoma, the superantigen, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the colon carcinoma-reactive monoclonal antibody C242. In the present study the effector mechanisms involved in the anti-tumor response to C242 Fab-SEA were characterized. Immunohistochemistry and computer-aided image analysis were used in studies of cryopreserved tumor tissue to evaluate the phenotype of infiltrating cells and their cytokine profiles in response to therapy. Human T cells and monocytes were recruited to the tumor area and penetrated the entire tumor mass within hours after injection of C242 Fab-SEA. The production of cytokines at the single-cell level was found to be dominated by tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor, and transforming growth factor-beta, whereas IL-1-alpha, IL-1ra, IL-1 beta, TNF-beta, IL-3, IL-6, and IL-8 were undetectable. Most of the TNF-alpha, IL-2, IL-12, and IFN-gamma were made by the infiltrating human leukocytes, while the colon carcinoma cells were induced to produce IL-4, IL-10, and TNF-alpha. Up-regulation of IFN-gamma receptors and TNF R p60 receptors was found, while the TNF R p80 receptor was absent. The cytokine production, T cell infiltration, and CD95 Fas receptor expression concomitantly occurred to induce programmed cell death in the tumor cells. This was followed by a strong reduction of the tumor mass that was seen within 24 h after C242 Fab-SEA infusion. These findings demonstrate that antibody-superantigen proteins efficiently recruit tumor-infiltrating lymphocytes actively producing a variety of cytokines likely to be essential for the therapeutic effects observed in the model. Although the humanized SCID model has obvious limitations in its predictive value for treatment of human cancer, we believe that these results encourage clinical evaluation of antibody-targeted superantigens.
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PMID:Antibody-targeted superantigen therapy induces tumor-infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma. 856 49

IL-8 has been shown to be a human neutrophil and T cell chemoattractant in vitro. In an effort to assess the in vivo effects of IL-8 on human leukocyte migration, we examined the ability of rhIL-8 to induce human T cell infiltration using a human/mouse model in which SCID mice were administered human peripheral blood lymphocytes intraperitoneally, followed by subcutaneous injections of rhIL-8. rhIL-8 induced predominantly murine neutrophil accumulation by 4 h after administration while recombinant human macrophage inflammatory protein-1beta (rhMIP-1beta) induced both murine monocytes and human T cell infiltration during the same time period as determined by immunohistology. Interestingly, 72 h after chemokine administration, a marked human T cell infiltrate was observed in the IL-8 injection site suggesting that rhIL-8 may be acting indirectly possibly through a murine neutrophil-derived T cell chemoattractant. This hypothesis was confirmed using granulocyte-depleted SCID mice. Moreover, human neutrophils stimulated in vitro with IL-8 were found to release granule-derived factor(s) that induce in vitro T cell and monocyte chemotaxis and chemokinesis. This T cell and monocyte chemotactic activity was detected in extracts of both azurophilic and specific granules. Together, these results demonstrate that neutrophils store and release, upon stimulation with IL-8 or other neutrophil activators, chemoattractants that mediate T cell and monocyte accumulation at sites of inflammation.
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PMID:T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo. 862 78

The salient feature of solid tumor growth is the strict dependence on local angiogenesis. We have previously demonstrated that IL-8 is an angiogenic factor present in freshly isolated specimens of human non-small cell lung cancer (NSCLC). Using a model of human NSCLC tumorigenesis in SCID mice, we now report that IL-8 acts as a promoter of human NSCLC tumor growth through its angiogenic properties. Passive immunization with neutralizing antibodies to IL-8 resulted in more than 40% reduction in tumor size and was associated with a decline in tumor-associated vascular density and angiogenic activity. IL-8 did not act as an autocrine growth factor for NSCLC proliferation. The reduction in primary tumor size in response to neutralizing antibodies to IL-8 was also accompanied by a trend toward a decrease in spontaneous metastasis to the lung. These data support the notion that IL-8 plays a significant role in mediating angiogenic activity during tumorigenesis of human NSCLC, thereby offering a potential target for immunotherapy against solid tumors.
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PMID:Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. 867 90

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

Although IL-8 has been reported to be a chemoattractant for T cells in vivo and in vitro, this has been a controversial issue. By using freshly purified human T cells (>90% CD3(+)), we demonstrated consistent T-cell migration in response to recombinant human IL-8 in vitro. However, highly purified T cells, when incubated at 37°C for more than 12 h or cultured overnight in the presence of anti-CD3 antibody, showed a markedly reduced capacity to migrate in response to IL-8. This reduction in chemotaxis was associated with a decrease in binding of 125I-IL-8 to T cells. Northern blots showed that freshly purified T cells expressed both IL-8 receptor type A and type B transcripts. Steady-state levels of mRNA for IL-8RA and IL-8RB in T cells were progressively reduced with time by incubation of the cells at 37°C with or without anti-CD3. The inability of cultured T cells to migrate in response to IL-8 accounts for the contradictory published reports on this issue. In vivo administration of IL-8 in rats resulted in the infiltration at the injection site of neutrophils followed by T cells, and this later T-cell infiltration was reported to be partially blocked by selective depletion of neutrophils. These observations raised the possibility that IL-8 may trigger neutrophils to release a factor(s) that may also participate in the T-cell recruitment. Neutrophil granule proteins, defensins, and CAP37/azurocidin released upon stimulation of cells by IL-8 were shown to induce human T-cell migration in vitro. Subcutaneous injection of defensins into SCID mice engrafted with human PBL resulted in significant infiltration by human CD3(+) T lymphocytes. These results indicate that IL-8 is able not only to act directly and induce migration of T lymphocytes that express IL-8 receptors, but also to act indirectly by activating neutrophils to release additional T-cell chemoattractants.
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PMID:IL-8-Induced T-Lymphocyte Migration: Direct as Well as Indirect Mechanisms 881 53

The protozoan parasite Entamoeba histolytica causes amebic dysentery and amebic liver abscess, diseases associated with significant morbidity and mortality worldwide. E. histolytica infection appears to involve the initial attachment of amebic trophozoites to intestinal epithelial cells, followed by lysis of these cells and subsequent invasion into the submucosa. A recent in vitro study (L. Eckmann, S. L. Reed, J. R. Smith, and M. F. Kagnoff, J. Clin. Invest. 96:1269-1279, 1995) demonstrated that incubation of E. histolytica trophozoites with epithelial cell lines results in epithelial cell production of inflammatory cytokines, including interleukin-1 (IL-1) and IL-8, suggesting that intestinal epithelial cell production of cytokines might play a role in the inflammatory response and tissue damage seen in intestinal amebiasis. To determine whether intestinal epithelial cell production of IL-1 and IL-8 occurs in response to E. histolytica infection in vivo and as an approach to studying the specific interactions between amebic trophozoites and human intestine, we used a SCID mouse-human intestinal xenograft (SCID-HU-INT) model of disease, where human intestinal xenografts were infected with virulent E. histolytica trophozoites. Infection of xenografts with E. histolytica trophozoites resulted in extensive tissue damage, which was associated with the development of an early inflammatory response composed primarily of neutrophils. Using oligonucleotide primers that specifically amplify human IL-1beta and IL-8, we could demonstrate by reverse transcription PCR that mRNA for both IL-1beta and IL-8 is produced by human intestinal xenografts in response to amebic infection. The increase in human intestinal IL-1beta and IL-8 in response to invasive amebiasis was confirmed by enzyme-linked immunosorbent assays specific for human IL-1beta and IL-8. Using immunohistochemistry, we confirmed that human intestinal epithelial cells were the source of IL-8 in infected xenografts and established that IL-8 production can occur at sites distal to areas of intestinal mucosal damage. These results demonstrate that human intestinal epithelial cells can produce inflammatory cytokines in response to infection in vivo and establish the SCID-HU-INT model as a system for studying the interactions between E. histolytica and human intestine.
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PMID:Human intestinal epithelial cells produce proinflammatory cytokines in response to infection in a SCID mouse-human intestinal xenograft model of amebiasis. 912 40

The properties of two candidate Salmonella typhi-based live oral typhoid vaccine strains, BRD691 (S. typhi Ty2 harboring mutations in aroA and aroC) and BRD1116 (S. typhi Ty2 harboring mutations in aroA, aroC, and htrA), were compared in a number of in vitro and in vivo assays. BRD1116 exhibited an increased susceptibility to oxidative stress compared with BRD691, but both strains were equally resistant to heat shock. Both strains showed a similar ability to invade Caco-2 and HT-29 epithelial cells and U937 macrophage-like cells, but BRD1116 was less efficient at surviving in epithelial cells than BRD691. BRD1116 and BRD691 were equally susceptible to intracellular killing within U937 cells. Similar findings were demonstrated in vivo, with BRD1116 being less able to survive and translocate to secondary sites of infection when inoculated into the lumen of human intestinal xenografts in SCID mice. However, translocation of BRD1116 to spleens and livers in SCID mice occurred as efficiently as that of BRD691 when inoculated intraperitonally. The ability of BRD1116 to increase the secretion of interleukin-8 following infection of HT-29 epithelial cells was comparable to that of BRD691. Therefore, loss of the HtrA protease in S. typhi does not seem to alter its ability to invade epithelial cells or macrophages or to induce proinflammatory cytokines such as IL-8 but significantly reduces intracellular survival in human intestinal epithelial cells in vitro and in vivo.
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PMID:Characterization of candidate live oral Salmonella typhi vaccine strains harboring defined mutations in aroA, aroC, and htrA. 991 80


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