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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we have shown that oncostatin M and interleukin-6 induce a dose- and time-dependent increase in fibrinogen levels in the conditioned medium of human hepatoma cells (HepG2). When HepG2 cells were treated simultaneously with oncostatin M or interleukin-6 and ciprofibrate (100 nmol/l), the production of fibrinogen in the conditioned media was strongly affected and a significant decrease in the mRNA levels of the fibrinogen beta chain was observed. Oncostatin-M- and interleukin-6-induced fibrinogen release was inhibited in a dose-dependent manner by ciprofibrate and, to lesser extent, by bezafibrate, fenofibric acid and clofibric acid. In vivo, increased plasma and platelet levels of fibrinogen were observed in genetically obese Zucker rats (fa/fa) compared with Zucker lean (fa/-) rats. In these rats, a 14-day oral treatment with ciprofibrate (10 mg/kg, per. os.) induced a statistically significant decrease (P > 0.05) in plasma concentrations of total cholesterol and triglyceride but also in plasma and platelet levels of fibrinogen. In order to determine the consequences of such an effect on fibrinogen, the ability of ciprofibrate to affect venous stasis was determined in a stasis-induced venous thrombosis model in Zucker rats. Under low thrombogenic challenge, ciprofibrate significantly inhibited thrombus formation (67+/-12%, P > 0.05), demonstrating for the first time that a potent hypolipemic compound exhibits an antithrombotic effect.
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PMID:Effect of ciprofibrate on fibrinogen synthesis in vitro on hepatoma cells and in vivo in genetically obese Zucker rats. 1045 14

Interleukin-11 (IL-11) belongs to the interleukin-6 (IL-6)-type subfamily of long-chain helical cytokines including IL-6, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M, and cardiotrophin-1, which all share the glycoprotein gp130 as a signal transducing receptor component. IL-11 acts on cells expressing gp130 and the IL-11 receptor (IL-11R) alpha-subunit (IL-11Ralpha). The structural epitopes of IL-11 required for the recruitment of the individual receptor subunits have not yet been defined. Based on the structure of CNTF, a three-dimensional model of human IL-11 was built. Using this model, 10 surface exposed amino acid residues of IL-11 were selected for mutagenesis using analogies to the well-characterized receptor recruitment sites of IL-6, CNTF, and LIF. The respective mutants of human IL-11 were expressed as soluble fusion proteins in bacteria. Their biological activities were determined on HepG2 and Ba/F3-130-11alpha cells. Several mutants with substantially decreased bioactivity and one hyperagonistic mutant were identified and further analyzed with regard to recruitment of IL-11Ralpha and gp130. The low-activity mutant I171D still binds IL-11Ralpha but fails to recruit gp130, whereas the hyperagonistic variant R135E more efficiently engages the IL-11R subunits. The low-activity mutants R190E and L194D failed to bind to IL-11Ralpha. These findings reveal a common mechanism of receptor recruitment in the family of IL-6-type cytokines and offer considerable perspectives for the rational design of IL-11 antagonists and hyperagonists.
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PMID:Definition of receptor binding sites on human interleukin-11 by molecular modeling-guided mutagenesis. 1050 96

Mouse oncostatin M (MuOSM) regulates the production of acute-phase proteins by hepatocytes as well as tissue inhibitor of metalloproteinases-1 (TIMP-1) production by fibroblasts in vitro. We have generated an adenovirus (Ad) encoding MuOSM and tested the effects of administration of recombinant AdMuOSM to mice in vivo. On intramuscular injection, AdMuOSM (5 X 10(7) plaque-forming units, pfu) induced an increase in serum levels of interleukin-6 (IL-6) as well as the acute-phase proteins serum amyloid A (SAP) and alpha1-acid glycoprotein (AGP) at day 1. SAP and AGP concentrations were elevated to greater levels at day 3 and decreased to near control levels at day 7. Intratracheal treatment with AdMuOSM induced TIMP-1 mRNA levels (as assessed by Northern blots) that corresponded to the presence of transgene MuOSM mRNA levels. TIMP-1 was elevated at day 1 and day 3 and less consistently at day 7 after administration. Intraperitoneal treatment with AdMuOSM also resulted in elevation of TIMP-1 mRNA in lung tissue. These results show that AdMuOSM can induce both local and systemic effects and demonstrate in vivo effects of OSM that are consistent with in vitro studies on acute-phase protein and TIMP-1 expression.
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PMID:Adenovirus vector expressing mouse oncostatin M induces acute-phase proteins and TIMP-1 expression in vivo in mice. 1054 60

Gp130 cytokine receptor is involved in the formation of multimeric functional receptors for interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor, and cardiotrophin-1. Cloning of the epitope recognized by an OSM-neutralizing anti-gp130 monoclonal antibody identified a portion of gp130 receptor localized in the EF loop of the cytokine binding domain. Site-directed mutagenesis of the corresponding region was carried out by alanine substitution of residues 186-198. To generate type 1 or type 2 OSM receptors, gp130 mutants were expressed together with either LIF receptor beta or OSM receptor beta. When positions Val-189/Tyr-190 and Phe-191/Val-192 were alanine-substituted, Scatchard analyses indicated a complete abrogation of OSM binding to both type receptors. Interestingly, binding of LIF to type 1 receptor was not affected, corroborating the notion that in this case gp130 mostly behaves as a converter protein rather than a binding receptor. The present study demonstrates that positions 189-192 of gp130 cytokine binding domain are essential for OSM binding to both gp130/LIF receptor beta and gp130/OSM receptor beta heterocomplexes.
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PMID:Identification of a gp130 cytokine receptor critical site involved in oncostatin M response. 1068 48

In this study we examine the activation of the latent Stat family of transcription factors by the gp130 family of cytokines in cell lines derived from human brain tumours. Of the cytokines tested, oncostatin M resulted in the most dramatic induction of Stat1 and Stat3 in all cell lines analysed, as assessed by the formation of protein/DNA complexes. Interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor also induced Stat complexes more selectively and to a lesser magnitude than oncostatin M. The kinetics of Stat1 and Stat3 activation was rapid and transient; the nuclear accumulation of DNA binding-proficient Stat protein was detected in the nucleus within minutes of cytokine induction. The transcriptional potential of the oncostatin M-activated Stat molecules was demonstrated in two glioma cell lines (U87-MG, SNB-19) by transient transfection experiments using a Stat-responsive reporter plasmid. Oncostatin M-dependent transcription from this reporter plasmid was reduced to uninduced levels by the inclusion of a dominant-negative Stat3 molecule, demonstrating that Stat molecules were responsible for the induction. These studies demonstrate that oncostatin M is the most potent activator of Stat molecules in a variety of brain tumour-derived cell lines, an observation that could have implications affecting the balance between proliferation/apoptosis of these cells.
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PMID:Activation of stat3 and stat1 DNA binding and transcriptional activity in human brain tumour cell lines by gp130 cytokines. 1070 21

The role of the interleukin-6 (IL-6) group of cytokines in differentiation of two lung adenocarcinoma cell lines has been examined using induction of alkaline phosphatase and expression of surfactant protein A. Oncostatin M was the most active and potent for alkaline phosphatase in A549 cells, with IL-6 having similar activity but less potency. Neither cytokine induced alkaline phosphatase in NCI-H441 cells, although induction was obtained with lung fibroblast-conditioned medium. Surfactant protein A was induced in NCI-H441 cells by conditioned medium and dexamethasone and, to a much lesser extent, by oncostatin M or IL-6. Induction of alkaline phosphatase and surfactant protein A were both dexamethasone-dependent, though some induction of surfactant protein A was obtained with interferon-alpha in the absence of dexamethasone. The activity present in lung fibroblast-conditioned medium suggests paracrine control, but this appears not to be due to oncostatin M or IL-6 as disabling antibodies to either cytokine were not inhibitory, and, although alkaline phosphatase was induced in A549 by both cytokines, it was only induced by conditioned medium in NCI-H441 cells. Furthermore, surfactant protein A was induced in H441 by conditioned medium to a much greater extent than by oncostatin M or IL-6. These data demonstrate that cytokines of the IL-6 group have potential as differentiation inducers in lung adenocarcinoma cells and that there is an equivalent paracrine factor(s) in lung fibroblast conditioned medium. As the production of this factor by fibroblasts is not enhanced by glucocorticoid, although the response of the target cell is, it would appear to be distinct from the fibrocyte pneumocyte factor previously described by Post et al 1984.
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PMID:Activity of growth factors in the IL-6 group in the differentiation of human lung adenocarcinoma. 1073 62

We have investigated the serum concentrations of interleukin-6 (IL-6) and two IL-6 family cytokines-oncostatin M (OSM) and leukemia inhibitory factor (LIF)-in 63 patients with B-cell chronic lymphocytic leukemia (B-CLL) and 17 healthy controls using the enzyme-linked immunosorbent assay (ELISA) method. Simultaneously, we measured the serum levels of the soluble forms of two subunits of the IL-6 receptor complex-ligand binding glycoprotein 80 (sIL-6R) and glycoprotein 130 (sgp130). The cytokines and receptors were evaluated in 25 untreated patients and 38 patients treated with cladribine (2-CdA), as well as in 17 healthy controls. We have correlated the serum levels of these proteins with Rai's clinical stage of the disease, the response to 2-CdA treatment and some hematological parameters. We have also evaluated the correlation of the IL-6 serum level with the concentration of OSM and IL-6 soluble receptors. IL-6 was measurable in 62/63 (98.4%), OSM in 20/25 (80%) of untreated and 14/38 (37.8%) of the treated patients. sIL-6R and sgp130 were detectable in all 63 patients and LIF in none of the CLL patients. IL-6 serum level in untreated patients was not significantly different as compared to its concentration in the control group (P>0.05). However, in the patients treated with 2-CdA the IL-6 level was significantly lower (P<0.02), and the lowest concentration was found in the patients with complete remission (CR; median 1.4pg/ml; P<0.02). The concentration of sIL-6R was significantly higher in untreated (median 61.8 ng/ml) and treated (median 50.1 ng/ml) CLL patients when compared to normal persons (median 41.2 ng/ml; P=0.04; P<0.001, respectively). There was no difference between the sIL-6R levels in the patients with CR and the healthy controls. In non-responders sIL-6R concentration was the highest and similar to its level in the untreated patients. OSM level was higher in the untreated patients (median 1.8pg/ml) than in the normal controls (median 0.0pg/ml; P<0.001) and in the CR patients (median 0.0pg/ml; P<0.03). The serum concentration of sgp130 was similar in the untreated (median 480 pg/ml) and treated (median 470 pg/ml) patients, as well as in the healthy persons (median 420 pg/ml; P>0.05). We have found significant positive correlation between the levels of sIL-6R and the lymphocytes count in CLL patients (p=0.423; P<0.001). In addition, sIL-6R and OSM serum concentrations correlated also with CLL Rai stage. In conclusion, the serum level of IL-6, OSM and sIL-6R, but not LIF and sgp130, are useful indicators of CLL activity.
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PMID:Serum levels of IL-6 type cytokines and soluble IL-6 receptors in active B-cell chronic lymphocytic leukemia and in cladribine induced remission. 1081 16

The related cytokines, interleukin-6 (IL-6), oncostatin M (OSM), and leukemia inhibitory factor (LIF) direct the formation of specific heteromeric receptor complexes to achieve signaling. Each complex includes the common signal-transducing subunit gp130. OSM and LIF also recruit the signaling competent, but structurally distinct OSMRbeta and LIFRalpha subunits, respectively. To test the hypothesis that the particularly prominent cell regulation by OSM is due to signals contributed by OSMRbeta, we introduced stable expression of human or mouse OSMRbeta in rat hepatoma cells which have endogenous receptors for IL-6 and LIF, but not OSM. Both mouse and human OSM engaged gp130 with their respective OSMRbeta subunits, but only human OSM also acted through LIFR. Signaling by OSMRbeta-containing receptors was characterized by highest activation of STAT5 and ERK, recruitment of the insulin receptor substrate and Jun-N-terminal kinase pathways, and induction of a characteristic pattern of acute phase proteins. Since LIF together with LIFRalpha appear to form a more stable complex with gp130 than OSM with gp130 and OSMRbeta, co-activation of LIFR and OSMR resulted in a predominant LIF-like response. These results suggest that signaling by IL-6 cytokines is not identical, and that a hierarchical order of cytokine receptor action exists in which LIFR ranks as dominant member.
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PMID:Receptor subunit-specific action of oncostatin M in hepatic cells and its modulation by leukemia inhibitory factor. 1085 24

Leukemia inhibitory factor (LIF) signals via the heterodimeric receptor complex comprising the LIF receptor alpha subunit (LIFRalpha) and the common signal transducing subunit for interleukin-6 cytokine receptors, gp130. This study demonstrates that in different cell types, the level of LIFRalpha decreases during treatment with LIF or the closely related cytokine oncostatin M (OSM). Moreover, insulin and epidermal growth factor induce a similar LIFRalpha down-regulation. The regulated loss of LIFRalpha is specific since neither gp130 nor OSM receptor beta shows a comparable change in turnover. LIFRalpha down-regulation correlates with reduced cell responsiveness to LIF. Using protein kinase inhibitors and point mutations in LIFRalpha, we demonstrate that LIFRalpha down-regulation depends on activation of extracellular signal-regulated kinase 1/2 and phosphorylation of the cytoplasmic domain of LIFRalpha at serine 185. This modification appears to promote the endosomal/lysosomal pathway of the LIFRalpha. These results suggest that extracellular signal-regulated kinase-activating factors like OSM and growth factors have the potential to lower specifically LIF responsiveness in vivo by regulating LIFRalpha half-life.
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PMID:Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase. 1085 40

Here, we demonstrate long-term cultivation of alkaline phosphatase-positive rat embryonic stem-like (RES) cell lines. RES cells were characterized by their typical growth in highly compacted cell clusters, which were found to be sensitive against enzymatic dissociation. RES cells expressed stage-specific embryonic antigen-1 (SSEA-1) and transcription factor Oct-4, but Oct-4 mRNA was detected at lower levels compared to mouse ES cells. Once established to tissue culture, RES cells were able to grow in the absence of feeder cells under clonal conditions. Cytokines of the interleukin-6 family known to maintain the undifferentiated state of mouse ES cells were comparatively analyzed for their capacity to maintain the undifferentiated growth of two cell lines, RES-1 and RES-15, in a clonal assay. Rat ciliary neurotrophic factor (rCNTF), human oncostatin M (hOSM), and interleukin-6 and soluble interleukin-6 receptor (IL-6/sIL-6R) were found to support clonal growth of RES cells, but the cytokines did not reach the efficiency of the colony forming ability of leukemia inhibitory factor (LIF). When RES-1 and RES-15 cells were cultivated without feeder cells, SSEA-1 expression was maintained after clonal growth in the presence of LIF and LIF + rCNTF, respectively. Oct-4 mRNA was significantly detected in RES-15 cells when cultivated in the absence of feeder cells in media substituted by LIF and/or IL-6/sIL-6R, as well as without cytokines. In summary, rat embryonic stem-like cell lines could be established from rat blastocysts and were able to proliferate as undifferentiated alkaline phosphatase-positive cells. Embryonal stem cell properties, such as SSEA-1 and Oct-4 expression, were maintained by members of the IL-6 family of cytokines, but most significantly by LIF.
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PMID:Establishment of SSEA-1- and Oct-4-expressing rat embryonic stem-like cell lines and effects of cytokines of the IL-6 family on clonal growth. 1089 87


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