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)

Interleukin-8 (IL-8) is a potent chemotactic factor for polymorphonuclear leukocytes (PMN). Here we examine whether PMN synthesize and release IL-8 in response to stimulation by selected inflammatory cytokines. PMN isolated from normal heparinized peripheral human blood were incubated in RPMI culture medium at 37 degrees C in 5% CO2, with and without granulocyte/macrophage colony-stimulating factor (GM-CSF). The culture supernatants were tested for chemotactic activity using a modified Boyden chamber. Immunoreactive IL-8 protein was measured by ELISA with a monoclonal antibody specific for IL-8. GM-CSF (0.01 to 50 ng/ml) stimulated PMN to produce chemotactic activity in a dose- and time-dependent manner. The amount of chemotactic activity reached maximal levels after 3 h of incubation with GM-CSF. Treatment of culture media supernatants with rabbit antiserum against IL-8 blocked the GM-CSF-induced chemotactic activity. IL-8 protein concentrations detected by ELISA closely paralleled the chemotactic bioactivity in both the dose-response and kinetic studies. Northern blot analysis of total RNA from PMN using a 30 mer oligonucleotide complementary to mRNA for IL-8 yielded a single 1.6-kb band. Its intensity increased 4-fold 2 h after treatment of PMN with GM-CSF. These data suggest that peripheral blood PMN can be stimulated by GM-CSF to synthesize and secrete bioactive IL-8. Since both IL-8 and GM-CSF accumulate in sites of acute inflammation, PMN may induce IL-8 gene expression in response to GM-CSF and thereby amplify the acute inflammatory response by recruiting additional PMN into inflammatory sites.
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PMID:Granulocyte/macrophage colony-stimulating factor stimulates human polymorphonuclear leukocytes to produce interleukin-8 in vitro. 841 54

In addition to T cells, NK cells, B cells, and monocytes, we provide new evidence that human polymorphonuclear neutrophils (PMN) can be functionally activated by IL-2 via binding to IL-2R beta expressed on the cell surface. Brief exposure of normal PMN to human rIL-2 enhanced both transcriptional and translational expression of TNF-alpha. The release of TNF-alpha protein by IL-2-treated PMN was inhibitable by a specific mAb against human IL-2-R beta. The response to IL-2 was dose and time dependent with the increase in TNF-alpha mRNA detected maximally 3 h after IL-2 exposure, followed by a continuous maintenance of high mRNA levels up to 18 h. The TNF-alpha mRNA was significantly increased above the medium control level, with as little as 10 U/ml of IL-2. Maximal transcription was obtained with 1000 U/ml of IL-2, which achieved the level observed with known neutrophil activating factors such as granulocyte-macrophage-CSF, IL-8, and Candida albicans. Using actinomycin D, it was found that new and continuous synthesis of a labile TNF-alpha mRNA was responsible for the observed high levels of transcripts. Of significance was the observation that cycloheximide could selectively modulate TNF-alpha mRNA transcription in neutrophils, depending on the cytokine used. Cycloheximide did not affect or alter TNF-alpha mRNA induction in IL-2-treated neutrophils but abrogated it in granulocyte-macrophage-CSF-treated neutrophils and superinduced transcription in C. albicans-treated neutrophils. Thus various control elements must be involved in the transcription of the TNF-alpha genes that are responsive to different cytokines and activating factors. The induction of TNF-alpha and functional activation of neutrophils by IL-2 is therefore an important immunomodulatory property of IL-2 that has not heretofore been recognized.
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PMID:Activation of tumor necrosis factor-alpha production from human neutrophils by IL-2 via IL-2-R beta. 843 29

The initiation and promulgation of chronic inflammation are controlled in part by the various pro-inflammatory and anti-inflammatory cytokines present at the site of injury. IFN-gamma and granulocyte-macrophage CSF (GM-CSF) are two cytokines that can contribute to the inflammatory state and possess both pro- and anti-inflammatory properties. However, the characterization of the interaction between GM-CSF-cultured monocytes and IFN-gamma is poorly documented. In this report we show that culture of human peripheral blood monocytes for up to 6 days in the presence of GM-CSF results in an eightfold increase in the level of IFN-gamma R expression, as determined by radioligand binding. The IFN-gamma R on these cells maintains a specificity typical of that observed in fresh monocytes. Only IFN-gamma, not IFN-alpha or -beta, blocks the binding of IFN-gamma to its receptor, and anti-IFN-gamma R antibodies block at least 80% of binding of IFN-gamma to these cultured cells. However, in spite of increased receptor expression, GM-CSF-cultured monocytes have a diminished response to IFN-gamma, as measured by the induction of the gene for IP-10 (a member of the platelet factor-4/IL-8 family). On the other hand, IFN-gamma-induced activation of the DNA-binding protein FcRF gamma is maintained in GM-CSF-cultured monocytes. Therefore, suppression of IFN-gamma-mediated IP-10 induction is not the result of a global abrogation of signal transduction across the IFN-gamma R but a more selective inhibition that appears to occur downstream of the receptor.
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PMID:Culture of human monocytes with granulocyte-macrophage colony-stimulating factor results in enhancement of IFN-gamma receptors but suppression of IFN-gamma-induced expression of the gene IP-10. 845 Feb 19

Peptide-specific IgG from a rabbit immunized with an alanine-lysine-proline-arginine ((ALA1)-tuftsin) containing 14-mer "ferritin" peptide neutralized rat liver ferritin inhibition of in vitro CSF-1-dependent monocytopoiesis. Antiferritin IgG similarly neutralized the inhibitory effect of ferritin but did not neutralize peptide inhibition of the in vitro myelopoietic response. No cross-reactivity between the respective antibodies and Ag was detected either by Western immunoblot or by competitive ELISA. Depletion of adherent cells before marrow cell culture significantly reduced the inhibitory effect of ferritin but did not influence peptide inhibition of CSF-1-stimulated colony formation. Adherent marrow cells and P388D1 cells treated with both CSF-1 and ferritin, but not either alone, produced inhibitory supernatant culture media that were neutralized by antipeptide but not antiferritin IgG. High resolution molecular sieve chromatography of the inhibitory adherent marrow cell and P388D1 supernatants resolved two peaks of 50 to 60 kDa and approximately 30 kDa in each. The inhibitory activity in all four peaks was neutralized by antipeptide but not antiferritin IgG. The ferritin/CSF inhibitors were not further characterized although identity with IL-6, IL-8, TNF-alpha, transforming growth factor-beta, and IFN-alpha/beta could be eliminated. The results indicate that ferritin inhibition of CSF-1-dependent monocytopoiesis is mediated by an endogenously produced inhibitor, or inhibitors, that shares antigenic similarity with the (ALA1)-tuftsin-containing 14-mer peptide and that adherent marrow cells, most likely monocytes or macrophages, produce the endogenous inhibitors in response to both CSF-1 and ferritin.
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PMID:Cytokine mediation of the suppressive effect of ferritin on colony-stimulating factor-1-dependent monocytopoiesis. 849 5

Recently we demonstrated that endothelins secreted from human keratinocytes act as intrinsic mitogens and melanogens for human melanocytes in UVB-induced melanosis. We show here that UVA-induced melanosis is associated with other keratinocyte-derived growth factors, secretion of which is specifically stimulated after exposure of human keratinocytes to UVA. Medium conditioned by UVA-exposed human keratinocytes elicited a significant increase in DNA synthesis by cultured human melanocytes in a UVA dose-dependent manner. Analysis of endothelin-1 and interleukin (IL)-1 alpha in the conditioned medium by ELISA, both of which are major keratinocyte-derived cytokines involved in UVB-associated melanocyte activation, revealed that UVA exposure did not cause human keratinocytes to stimulate the secretion of the two cytokines. In contrast, the levels of several other cytokines such as IL-6, IL-8 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were significantly increased in the conditioned medium of human keratinocytes after exposure to UVA at a dose of 1.0 J/cm2. The gel chromatographic profile of UVA-exposed keratinocyte-conditioned medium demonstrated that there were two factors (P-1 and P-2) with molecular masses of approx. 20 and 1 kDa respectively that stimulate DNA synthesis in human melanocytes, and the larger species (P-1) also increased melanization as assessed by [14C]thiouracil incorporation. Quantitative analysis of cytokines in chromatographic fractions by ELISA revealed the P-1 fraction to be consistent with the molecular mass profile of GM-CSF. Furthermore the stimulatory effect of the P-1 fraction on DNA synthesis in human melanocytes was neutralized by antibodies to GM-CSF, but not to basic fibroblast growth factor or stem cell factor. Binding and proliferation assays with recombinant GM-CSF demonstrated that human melanocytes possess specific binding sites for GM-CSF(Kd 2.11 nM; binding sites, 2.5-3.5 x 10(4) per cell), and recombinant GM-CSF at concentrations of more than 10 nM significantly stimulated DNA synthesis and melanization. These findings suggest that GM-CSF secreted by keratinocytes plays an essential role in the maintenance of melanocyte proliferation and UVA-induced pigmentation in the epidermis.
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PMID:Granulocyte/macrophage colony-stimulating factor is an intrinsic keratinocyte-derived growth factor for human melanocytes in UVA-induced melanosis. 857 2

Granulocyte-macrophage colony-stimulating factor (GM-CSF), in addition to being a haematopoietic growth factor, has been shown to stimulate in vitro the production of interleukins 1, 6 and 8 (IL-1, IL-6 and IL-8), tumour necrosis factor-alpha (TNF-alpha) and GM-CSF by polymorphonuclear cells (PMNs), alveolar macrophages (AMs), fibroblasts and endothelial cells of the lung, and the growth and differentiation of resident alveolar macrophages. The aim of this study was to establish whether recombinant GM-CSF (rhGM-CSF), administered subcutaneously at a dose of 5 micrograms.kg-1 for 3 days in five patients with unresectable non-small cell lung cancer before starting chemotherapy, induces an increase in the alveolar cell count, and whether these cellular lung variations may be related to increases in the above-mentioned cytokines. In the bronchoalveolar lavage fluid (BALF) total cell count, polymorphonuclear cells, neutrophils, and alveolar macrophages increased significantly in comparison with the baseline, and the extent of variation of the BAL cell count was considerably greater than that of the circulating leucocytes. The mean levels of all the cytokines increased, but a significant difference with respect to the basal condition was observed only for IL-6 and IL-8. After rhGM-CSF treatment, significant correlations were found between neutrophil counts and the levels of IL-6 and IL-8. In conclusion, rhGM-CSF administration induces a cellular expansion in the lung, and the neutrophil increase appears to be related to increased levels of IL-8.
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PMID:Blood cell redistribution in the lung after administration of recombinant human granulocyte-macrophage colony-stimulating factor. 857 86

The role of oncostatin M (OM) in modulating production of cytokines by connective tissue cells is largely unexplored. We have examined the effects of stimulating fibroblast cultures derived from human synovium and from normal lung with OM alone or in combination with IL-1, IL-1 alpha (or IL-1 beta) at 1 or 5 ng/ml, stimulated production of high levels of granulocyte-macrophage CSF (GM-CSF), IL-8, and IL-6 protein. At various concentrations (0.1-50 ng/ml), OM alone failed to significantly enhance protein or mRNA levels of GM-CSF, IL-8, IL-6, or G-CSF after 18 h of stimulation. When combined with IL-1 alpha or -beta, OM caused a dose-dependent inhibition of the IL-1-induced level of IL-8 and GM-CSF protein and mRNA expression, whereas IL-6 production was simultaneously enhanced. In contrast, when IL-6 or leukemia inhibitory factor (two other cytokines that share gp130 receptor components with OM) were used in a similar fashion in combination with IL-1 alpha, neither cytokine consistently altered the IL-1-induced levels of IL-8, GM-CSF, or IL-6. In addition, only OM and not IL-6 or leukemia inhibitory factor was able to induce STAT-1 nuclear factor binding to DNA in stimulated fibroblast extracts as measured by electrophoretic mobility shift assay. These results suggest that OM can significantly alter cytokine profiles of stimulated fibroblasts and may play a unique role in modulating cytokine production by these cells at sites of inflammation.
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PMID:Oncostatin M inhibits IL-1-induced expression of IL-8 and granulocyte-macrophage colony-stimulating factor by synovial and lung fibroblasts. 859 83

To study the capacity and regulation of cytokine production by normal peripheral blood eosinophils, we isolated eosinophils from healthy individuals and stimulated them with immobilized Ig or TNF-alpha, with or without exogenous IL-5. By reverse transcription-PCR, uncultured, freshly isolated eosinophils constitutively expressed mRNA for IL-4, IL-10, and TGF-beta1. Eosinophils stimulated by immobilized secretory IgA, immobilized IgA, immobilized IgG, or TNF-alpha for 3 h expressed mRNA encoding IL-3, IL-4, IL-8, IL-10, granulocyte-macrophage CSF, TNF-alpha, TGF-beta, and RANTES. The mRNA for IL-2, IL-5, or IFN-gamma was not detected. IL-4 and IL-10 protein, but not IL-8, were measurable in lysates of fresh eosinophils or eosinophils cultured with medium alone for 24 h. Eosinophils incubated with immobilized Ig or TNF-alpha released IL-8 protein into the supernatants. In contrast, IL-4 and IL-10 proteins were not detectable. Soluble secretory IgA immune complexes also induced degranulation, as measured by eosinophil-derived neurotoxin, and IL-8 release, but not IL-4 or IL-10 release, from eosinophils. Release of IL-8 protein and storage of IL-4 and IL-10 proteins were enhanced by exogenous IL-5 and inhibited by a transcription inhibitor, actinomycin D. Degranulation of stored granule proteins was not affected by actinomycin D. Therefore, normal peripheral blood eosinophils can transcribe and synthesize several cytokines, including IL-4, IL-8, and IL-10; some are stored, and some are released. These cytokines may play important roles in modulating immune responses in diseases associated with eosinophils.
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PMID:Constitutive production of IL-4 and IL-10 and stimulated production of IL-8 by normal peripheral blood eosinophils. 864 35

Lym-1 is a murine IgG2a monoclonal antibody that recognizes a polymorphic variant of HLA-DR antigens on malignant B cells, with minimal cross-reactivity with normal tissues. Because it can be safely administered in vivo, a detailed knowledge of its ability to recruit and trigger the antitumor immune effector systems is required to optimize potential serotherapeutic approaches in B-lymphoma patients. By using Raji cells as a model of B-lymphoma targets, we found that Lym-1 activates complement-mediated lysis efficiently. Moreover, Lym-1 was capable of triggering the antibody-dependent cellular cytolysis (ADCC) by peripheral blood mononuclear cells (MNCs). On the contrary, it failed to trigger neutrophilic polymorphonuclear leukocyte (PMN)-mediated ADCC activity. In an attempt to enhance Lym-1 ADCC by MNCs and PMNs, nine biologic response modifiers were tested. MNC-mediated Lym-1 ADCC was significantly stimulated by interleukin-2 (IL-2) and unaffected by other mediators, including gamma-interferon (gamma-IFN), tumor necrosis factor a (TNFalpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF). On the other hand, PMN-mediated Lym-1 ADCC was induced or significantly augmented by various cytokines, such as GM-CSF, TNFalpha, and gamma-IFN, and chemotaxins, such as formyl peptides (FMLP), complement fragment C5a, and IL-8. Both MNC- and PMN-mediated ADCC was unaffected by granulocyte colony-stimulating factor (G- CSF) and insulin-like growth factor-1 (IGF-1). Finally, only GM-CSF and TNFalpha augmented the number of PMNs actually engaged in the binding of Raji target cells. The findings presented here, in particular those showing stimulatory activity of biologic response modifiers, may inspire new attempts for developing Lym-1 antibody-based approaches to the therapy of B lymphomas.
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PMID:Monoclonal Lym-1 antibody-dependent lysis of B-lymphoblastoid tumor targets by human complement and cytokinine-exposed mononuclear and neutrophilic polymorphonuclear leukocytes. 865 30

Expression of IL-2R was examined on human fibroblasts isolated from different tissues. By specific binding assay it is shown that [125I]IL-2 bound to subconfluent adult bone marrow and embryonic skin and lung fibroblasts. The presence of binding sites for IL-2 was also confirmed by immunofluorescence and flow cytometry analysis using mAbs specific for the p55 IL-2R alpha (anti-CD25), p75 IL-2R beta, and p64 IL-2R gamma subunits. Fibroblasts also constitutively transcribed the genes coding for IL-2R alpha and IL-2R beta and accumulated their respective mRNAs but failed to exhibit the IL-2R gamma-chain on the mRNA and protein level. Although addition of IL-2 to fibroblast cultures did not significantly alter growth kinetics of these cells, the IL-2R complex displayed by fibroblasts appeared to be functional in that addition of IL-2 to these cells led to enhanced expression of the JE gene coding for the monocyte chemoattractant protein-1 (MCP-1). Enhancement of fibroblast MCP-1/JE gene expression by IL-2 appeared to result from delayed MCP-1/JE mRNA decay rather than as a consequence of an acceleration of the MCP-1/JE gene transcription rate. IL-2 had, however, no effect on the expression of other cytokine genes including IL-1, IL-5, IL-6, IL-7, IL-8, IL-9, granulocyte-macrophage-CSF, macrophage-CSF or TNF. These observations suggest that the range of cellular targets of IL-2 is broader than originally appreciated. IL-2 may thus serve to integrate fibroblasts and monocytes into a coordinated response of the connective tissue initiated by T lymphocytes.
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PMID:Human fibroblasts express functional IL-2 receptors formed by the IL-2R alpha- and beta-chain subunits: association of IL-2 binding with secretion of the monocyte chemoattractant protein-1. 875 38


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