Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Women with breast cysts lined by apocrine epithelium (intracystic Na/K < 3) may have a higher risk of developing breast cancer than those whose breast cysts are lined by "flattened" epithelium (intracystic Na/K < 3). In this study, the concentrations of the cytokines, oncostatin M (OSM), interleukin 2 (IL-2), interleukin 6 (IL-6) and interleukin 8 (IL-8) were measured in breast cyst fluid, OSM, IL-2 and IL-6 having been shown to have growth-inhibitory actions on tumour cells. All cytokines were measured by "sandwich" enzyme immunoassays. IL-2 was not detectable in breast cyst fluid. OSM, IL-6 and IL-8 concentrations were significantly higher in the high-electrolyte-ratio group. Although significant positive correlations were found between OSM and IL-6, OSM and IL-8, OSM and Na/K, IL-6 and IL-8, IL-6 and Na/K and IL-8 and Na/K when all samples were analysed together, analysis of the correlations between these analytes in each subgroup separately suggests that the control of production of these cytokines or the mechanism of entry into cyst fluid is likely to be different for the 2 cyst types. The significantly higher intracystic concentrations of OSM and IL-6 in the high-electrolyte-ratio group may partly explain the lower risk of breast cancer in this group of women.
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PMID:Oncostatin M, interleukin 2, interleukin 6 and interleukin 8 in breast cyst fluid. 792 43

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

Nontransformed stromal colony-derived cell lines (CDCLs) consist of a pure stromal cell population that differentiates following a vascular smooth muscle cell repertoire, and whose in vivo counterpart is that of myoid cells found in adult and fetal human bone marrow cords. We studied the cytokine expression by reverse-transcriptase polymerase chain reaction (RT-PCR) from pooled fast-growing clones from 10 different bone marrow samples. RT-PCR indicated that 30 cytokines (out of 42 studied) were expressed by CDCLs (20 after medium renewal and hydrocortisone renewal, three after addition of interleukin I beta (IL-1 beta) and seven in only part of the CDCL layers examined). The cytokines expressed comprised mediators known to be involved in the maintenance of early and late hematopoiesis (IL-1 alpha and IL-beta, IL-6, IL-7, IL-8, IL-11 and IL-13; colony-stimulating factors, thrombopoietin, erythropoietin, stem cell factor, fit 3-ligand, hepatocyte cell growth factor, tumor necrosis factor alpha, leukemia inhibitory factor, transforming growth factors beta 1 and beta 3; and macrophage inflammatory protein 1 alpha), angiogenic factors (fibroblast growth factors 1 and 2, vascular endothelial growth factor) and mediators whose usual target (and source) is the connective tissue-forming cells (platelet-derived growth factor A, epidermal growth factor, transforming growth factors alpha and beta 2, oncostatin M and insulin-like growth factor 1), or neuronal cells (nerve growth factor). The cytokines not expressed were lymphokines (IL-2, IL-3, IL-4, IL-5, IL-9, IL-10, and IL-12 and interferon gamma) or mediators synthesized by macrophages (inhibin, activin, platelet-derived growth factor B, and IL-1 receptor antagonist). This study complements the description of the phenotype of the myoid cells, confirming that these cells are the marrow connective tissue-forming cells; moreover, this work suggests that stromal control of hematopoiesis is multifactorial and that myoid cells are involved in the control of marrow angiogenesis and innervation.
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PMID:The broad spectrum of cytokine gene expression by myoid cells from the human marrow microenvironment. 909 Jul 90

Oncostatin M is a member of the IL-6 family of cytokines that is primarily known for its effects on cell growth. Endothelial cells have an abundance of receptors for oncostatin M, and may be its primary target. We determined if oncostatin M induces a key endothelial cell function, initiation of the inflammatory response. We found that subcutaneous injection of oncostatin M in mice caused an acute inflammatory reaction. Oncostatin M in vitro stimulated: (a) polymorphonuclear leukocyte (PMN) transmigration through confluent monolayers of primary human endothelial cells; (b) biphasic PMN adhesion through rapid P-selectin expression, and delayed adhesion mediated by E-selectin synthesis; (c) intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 accumulation; and (d) the expression of PMN activators IL-6, epithelial neutrophil activating peptide-78, growth-related cytokine alpha and growth-related cytokine beta without concomitant IL-8 synthesis. The nature of the response to oncostatin M varied with concentration, suggesting high and low affinity oncostatin M receptors independently stimulated specific responses. Immunohistochemistry showed that macrophage-like cells infiltrating human aortic aneurysms expressed oncostatin M, so it is present during a chronic inflammatory reaction. Therefore, oncostatin M, but not other IL-6 family members, fulfills Koch's postulates as an inflammatory mediator. Since its effects on endothelial cells differ significantly from established mediators like TNFalpha, it may uniquely contribute to the inflammatory cycle.
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PMID:Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. 920 68

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.
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PMID:Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. 951 48

Neovascularization of the atherosclerotic plaque is responsible for its weakening and consequently for the complications of vascular disease. Macrophages are a source of growth factors that can modulate angiogenesis. In this study, we analyzed the effect of oncostatin M (OSM) on angiogenesis, as it could be involved in the development of atherosclerosis. The effect of OSM was compared with those of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). On human dermal microvasculature endothelial cells (HMEC-1s), OSM (22.5 to 112.5 pmol/L) induced a dose-dependent increase in cell proliferation greater than that induced by the classic angiogenic factors vascular endothelial growth factor (VEGF; 543 pmol/L) and basic fibroblast growth factor (bFGF; 1.1 nmol/L). LIF (19 to 475 pmol/L) induced only a 30% increase in cell proliferation, and IL-6 had no effect. Furthermore, in a modified Boyden-chamber model, OSM, LIF, and IL-6 were chemoattractant for HMEC-1s. In a tridimensional gel of fibrin, OSM increased tube formation and tube length, which were already noticeable by day 3. LIF and IL-6 induced a weaker effect that was only obvious by day 10. The angiogenic effect of OSM was also demonstrated in vivo in a rabbit corneal model: OSM was more potent than LIF, the length of the neovessels being longer with OSM than with LIF, whereas IL-6 was without effect. We tested factors that could be involved in the proliferative effect of OSM on HMEC-1s. OSM induced only a slight increase in the urokinase receptor and a 60% increase in VEGF secretion, whereas it does not modify IL-8 secretion or bFGF levels. The effect of OSM seems to depend on endothelial cell origin and cell species: OSM (up to 112.5 pmol/L) did not induce human umbilical vein endothelial cell proliferation and even had a small inhibitory effect (17%) on calf pulmonary artery endothelial cells. In conclusion, OSM induces an angiogenic effect on capillary endothelial cells, which could be, at least in part, implicated in pathological processes such as atherosclerosis or tumor growth.
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PMID:Oncostatin M induces angiogenesis in vitro and in vivo. 1044 61

Exposure to ambient air pollution particles with a diameter of < 10 microm (PM(10)) has been associated with increased cardiopulmonary morbidity and mortality. We postulate that these adverse health effects are related to proinflammatory mediators produced in the lung and released into the circulation where they initiate a systemic inflammatory response. The present study was designed to determine if alveolar macrophages (AMs) and primary human bronchial epithelial cells (HBECs) interact to amplify the production of certain cytokines when exposed to ambient PM(10) (EHC-93). Candidate cytokines were measured at the mRNA level using a RNase protection assay and at the protein level by enzyme-linked immunosorbent assay (ELISA). When AM/HBEC cocultures were exposed to 100 microg/ml of PM(10), levels of tumor necrosis factor (TNF)-alpha, granulocyte macrophage colony stimulating factor (GM-CSF), interleukin (IL)-1beta, IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM), and IL-8 mRNA increased within 2 h (P < 0.05) and 8 h following exposure compared with control cells. GM-CSF mRNA expression was more rapidly induced in cocultured cells compared with HBECs or AMs alone. The concentrations of TNF-alpha, GM-CSF, IL-1beta, IL-6, and IL-8 in the cocultured supernatants collected after 24 h PM(10) exposure increased significantly compared with control cells. There was a significant synergistic effect between AMs and HBECs in the production of GM-CSF and of IL-6 (P < 0.05). Instillation of supernatants from HBECs cultured with PM(10) into lungs of rabbits failed to increase circulating band cell counts or stimulate the bone marrow. However, those from AM/HBEC cocultures exposed to PM(10) increased circulating band cell counts (P < 0.05) and shortened the transit time of polymorphonuclear leukocytes (PMNs) through the bone marrow compared with control co-cultures (P < 0.01). These results suggest that the interaction between AMs and HBECs during PM(10) exposure contributes to the production of mediators that induce a systemic inflammatory response.
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PMID:Interaction of alveolar macrophages and airway epithelial cells following exposure to particulate matter produces mediators that stimulate the bone marrow. 1209 Dec 43

Recently, we identified that regulation of leukocyte recruitment by IL-6 requires shedding of the IL-6R from infiltrating neutrophils. In this study, experiments have examined whether other IL-6-related cytokines possess similar properties. Levels of oncostatin M (OSM) and leukemia inhibitory factor were analyzed in patients with overt bacterial peritonitis during the first 5 days of infection. Although no change in leukemia inhibitory factor was observed throughout the duration of infection, OSM was significantly elevated on day 1 and rapidly returned to baseline by days 2-3. The source of OSM was identified as the infiltrating neutrophils, and OSM levels correlated both with leukocyte numbers and i.p. soluble IL-6R (sIL-6R) levels. FACS analysis revealed that OSM receptor beta expression was restricted to human peritoneal mesothelial cells. Stimulation of human peritoneal mesothelial cells with OSM induced phosphorylation of gp130 and OSM receptor beta, which was accompanied by activation of STAT3 and secretion of CC chemokine ligand 2/monocyte chemoattractant protein-1 and IL-6. Although OSM itself did not modulate CXC chemokine ligand 8/IL-8 release, it effectively suppressed IL-1beta-mediated expression of this neutrophil-activating CXC chemokine. Moreover, OSM synergistically blocked IL-1beta-induced CXC chemokine ligand 8 secretion in combination with the IL-6/sIL-6R complex. Thus suggesting that OSM and sIL-6R release from infiltrating neutrophils may contribute to the temporal switch between neutrophil influx and mononuclear cell recruitment seen during acute inflammation.
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PMID:Secretion of oncostatin M by infiltrating neutrophils: regulation of IL-6 and chemokine expression in human mesothelial cells. 1239 Dec 43

Previously, we elucidated the intracellular mechanisms by which neutrophil elastase (NE) up-regulates inflammatory gene expression in bronchial epithelial cells. In this study, we examine the effects of both IL-1 and NE on inflammatory gene expression in 16HBE14o- bronchial epithelial cells and investigate approaches to abrogate these inflammatory responses. IL-1 induced IL-8 protein production in time- and dose-dependent fashions, an important observation given that IL-8 is a potent neutrophil chemoattractant and a key inflammatory mediator. IL-1 and NE were shown to activate the p38 MAPK pathway in 16HBE14o- cells. Western blot analysis demonstrated IL-1R-associated kinase 1 (IRAK-1) degradation in response to stimulation with both IL-1 and NE. In addition, the expression of dominant negative IRAK-1 (IRAK-1delta), IRAK-2delta, or IRAK-4delta inhibited IL-1- and NE-induced NF-kappaB-linked reporter gene expression. Dominant negative versions of the intracellular adaptor proteins MyD88 (MyD88delta) and MyD88 adaptor-like (Mal P/H) abrogated NE-induced NF-kappaB reporter gene expression. In contrast, only MyD88delta was found to inhibit IL-1-induced NF-kappaB reporter activity. We also investigated the vaccinia virus proteins, A46R and A52R, which have been shown to antagonize IL-1 signaling. Transfection with A46R or A52R cDNA inhibited IL-1- and NE-induced NF-kappaB and IL-8R gene expression and IL-8 protein production in primary and transformed bronchial epithelial cells. Furthermore, cytokine array studies demonstrated that IL-1 and NE can up-regulate the expression of IL-6, oncostatin M, epithelial cell-derived neutrophil activating peptide-78, growth-related oncogene family members, vascular endothelial growth factor, and GM-CSF, with induction of these proteins inhibited by the viral proteins. These findings identify vaccinia virus proteins as possible therapeutic agents for the manifestations of several inflammatory lung diseases.
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PMID:Viral inhibition of IL-1- and neutrophil elastase-induced inflammatory responses in bronchial epithelial cells. 1630 69

We previously reported an increase in signal transducer and activator of transcription 3 (Stat3) activation in keloid fibroblasts, which contributes to collagen production, cell proliferation, and migration. We further investigated the effect of epithelial-mesenchymal interaction on Stat3 in normal and keloid fibroblasts in noncoculture and coculture conditions. pY705 Stat3 was higher in keloid fibroblasts compared to normal fibroblasts in noncoculture. However, a more drastic decrease in pY705 Stat3 was observed in keloid fibroblasts compared to normal fibroblasts when cocultured with their respective keratinocytes over 5 days. To explore this paracrine effect, we examined the secretion of cytokines by cytokine arrays. Altered cytokine production was detected in keloid fibroblasts and keratinocytes, either in noncoculture or coculture conditions. IL-6, IL-8, monocyte chemoattractant protein-1, tissue inhibitor of metalloproteinases (TIMPs)-1, and TIMP-2 were major cytokines detected. Angiogenin, oncostatin M (OSM), vascular endothelial cell growth factor, IGF-binding protein-1, osteoprotegerin, and transforming growth factor-beta2 were present in keloid keratinocyte-fibroblast coculture, but absent in normal keratinocyte-fibroblast coculture. Only IL-6 and OSM stimulated strong pY705 Stat3 and cell proliferation in both normal and keloid fibroblasts. Other cytokines increased proliferation of keloid fibroblasts, but not normal fibroblasts, suggesting an altered state in keloid fibroblasts. Multiple cytokines likely contribute to keloid pathogenesis and a combinatorial neutralizing antibody/cytokine therapy may be effective in ameliorating keloid scars.
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PMID:Cytokine profiling and Stat3 phosphorylation in epithelial-mesenchymal interactions between keloid keratinocytes and fibroblasts. 1903 37


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