UNIPROT:P05231 - FACTA Search

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

T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and beta (beta1 and beta4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6beta4 lined the basal surface of TEC monolayers, whereas 3beta1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3beta1 and 6beta4 became highly enriched also at the boundaries with adherent thymocytes. Functional studies performed with MoAbs anti-beta1 and -beta4 integrins showed that beta1, and, to a much lower extent, beta4 heterodimers are involved in the TEC-thymocyte adhesion. Thymocyte contact or MoAb-mediated ligation of 3, 6, beta1, and beta4 integrins was investigated as a potential inducer of intracellular signaling in TEC. Thymocyte adhesion or cross-linking of MoAbs bound to integrins clustered at the TEC/thymocyte contact sites led to activation of interleukin-6 (IL-6) gene transcription factors, namely NF-IL6 serine phosphorylation and NF-kappaB nuclear targeting, as well as to increased IL-6 secretion. We propose that integrin clustering occurring during TEC-thymocyte contacts modulates in TEC the gene expression of a cytokine involved in thymocyte growth and functional differentiation.
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PMID:Thymocyte contact or monoclonal antibody-mediated clustering of 3beta1 or 6beta4 integrins activate interleukin-6 (IL-6) transcription factors (NF-kappaB and NF-IL6) and IL-6 production in human thymic epithelial cells. 980 69

Heparin-coated cardiopulmonary bypass circuits reduce the inflammatory response to cardiopulmonary bypass circuit, improve biocompatibility and may protect the postoperative hemostasic mechanisms in routine coronary bypass operations. 'High-dose' aprotinin reduces bloodloss, transfusion needs, and re-explorations as a result of bleeding, and may have an additional role in reducing the inflammatory response of the body to cardiopulmonary bypass circuit. It has not been established, however, if the addition of a heparin-coated circuit to the intraoperative administration of 'high dose' aprotinin further reduces the whole-body inflammatory response to cardiopulmonary bypass circuit and improves the postoperative clinical course of the patients who are undergoing coronary surgery. Thirty patients undergoing primary elective coronary artery bypass grafting were studied. All the patients received, intraoperatively, the serine-protease inhibitor aprotinin according to the 'Hammersmith' protocol and full heparin dose. Patients were randomly allocated to be treated either with a circuit completely coated with surface-bound heparin (n = 15) or with an uncoated, but otherwise identical, circuit (n = 15). Differences in the clinical course of the two groups of patients, as well as differences in the behavior of hematological and inflammatory (interleukin-6 (IL-6) and C-reactive protein) factors before, during and after bypass, were analyzed. There were no significant differences between the two groups in terms of bleeding and transfusional requirements, the time spent on a ventilator, or in duration of stay in the intensive care unit (ICU). In all patients, a significant increase in the total white blood cell count, neutrophils, serum IL-6 and C-reactive protein occurred in relation to cardiopulmonary bypass. This was not influenced by heparin precoating of the circuit. In addition, there was an increase in the monocyte count during follow-up, and there was a trend towards higher monocyte counts in the patients who were treated with heparin-coated circuits. These results suggest that the addition of a heparin-coated circuit to the intraoperative 'high-dose' aprotinin therapy probably had little influence on the clinical course and on the time-course of the inflammatory parameters of the adult patients undergoing primary coronary surgery with a full heparinization protocol.
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PMID:'High dose' aprotinin and heparin-coated circuits: clinical efficacy and inflammatory response. 1007 71

Exposure of primary human lung fibroblasts (HLF) to interleukin-6 (IL-6) rapidly induced Stat3 (signal transducers and activators of transcription 3) tyrosine phosphorylation. In these cells, alpha-thrombin did not induce tyrosine phosphorylation of Stat3; however, it potently induced its serine phosphorylation. Interestingly, a short pretreatment of cells with alpha-thrombin significantly inhibited IL-6-induced tyrosine phosphorylation of Stat3. The inhibition by alpha-thrombin was attenuated if cells were pretreated with U0126, a specific inhibitor of the mitogen-activated protein (MAP) kinase kinase 1 (MAPKK1). Exposure of HLF cells to IL-6 induced a twofold increase in gp130 mRNA levels; however, alpha-thrombin inhibited this IL-6-induced response almost to control levels. These results demonstrate, for the first time, that in HLF cells alpha-thrombin inhibits IL-6-induced Stat3 signaling via activation of MAPKK1 and that this cross-talk regulates IL-6-induced gp130 gene expression.
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PMID:alpha-thrombin inhibits interleukin-6-induced Stat3 signaling and gp130 gene expression in primary cultures of human lung fibroblasts. 1008 Sep 49

The avascular cornea has limited access to plasma proteins, including plasminogen, a protein that is synthesized by the liver and supplied to most tissues via the blood. Recent experiments by others using plasminogen-deficient mice revealed the importance of plasmin, the active form of plasminogen, for the maintenance of the normal cornea and for corneal wound healing [Kao, Kao, Bugge, Kaufman, Kombrinck, Converse, Good and Degan (1998) Invest. Ophthalmol. Vis. Sci. 39, 502-508; Drew, Kaufman, Kombrinck, Danton, Daugherty, Degen and Bugge (1998) Blood 91, 1616-1624]. In the present experiments, plasmin was identified as a major serine proteinase in the human cornea. The major plasminogen and plasmin forms on non-reducing zymograms and Western blots had Mr values of 76x10(3) and 85x10(3), with minor forms of Mr 200x10(3), 135x10(3), 68x10(3) and 45x10(3). Angiostatin-like peptides with Mrs of 48x10(3), 45x10(3) and 38x10(3) were observed which bound to lysine-Sepharose and reacted with anti-plasminogen monoclonal antibodies directed towards kringle domains 1-3 of plasminogen. The cornea contained 1.1+/-0.15 microgram of plasminogen+plasmin/cornea, or 0.54+/-0.05 microgram of plasminogen+plasmin/mg of protein. Cornea conditioned medium contained nine times the amount of plasminogen+plasmin that could be extracted from the cornea. These data suggested that corneal cells, unlike most extrahepatic cells, synthesize plasminogen. The synthesis of plasminogen by the cornea was confirmed by immunoprecipitation of metabolically labelled plasminogen, sequencing of its cDNA obtained by reverse transcriptase-PCR and inhibition of protein synthesis. Interleukins-1alpha and -1beta stimulated corneal plasminogen synthesis 2-3-fold; however, interleukin-6 decreased corneal plasminogen synthesis by approx. 40% at early times after addition of the cytokine. By 24 h of culture, no differences were noted in the presence and absence of interleukin-6. Thus the cornea can synthesize plasminogen and regulate its synthesis in response to its environment, including cytokines induced in the cornea by injury and inflammation. Therefore the cornea can control the amount of plasminogen, the precursor of both plasmin and angiostatin.
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PMID:Extrahepatic synthesis of plasminogen in the human cornea is up-regulated by interleukins-1alpha and -1beta. 1021 10

Stat3 is activated by phosphorylation on Tyr-705, which leads to dimer formation, nuclear translocation, and regulation of gene expression. Serine phosphorylation of Stat3 by mitogen-activated protein kinase has also been observed in cells responding to epidermal growth factor and shown to affect its tyrosine phosphorylation and transcriptional activity. Serine phosphorylation of Stat3 is also induced by interleukin-6 (IL-6) stimulation, which is shown to be independent of mitogen-activated protein kinase and sensitive to the Ser/Thr kinase inhibitor H7. In this study, we investigated whether protein kinase C (PKC) is the kinase that is induced and responsible for Stat3 serine phosphorylation by IL-6 stimulation and which isoform of PKCs is likely to be involved. Here, we report that Stat3 was specifically associated with PKC delta in vivo in an IL-6-dependent manner in several cell types. Furthermore, Stat3 was phosphorylated by PKC delta in vivo on Ser-727, which could be inhibited either by a specific PKC delta inhibitor or by a dominant-negative mutant of PKC delta. Finally, we showed that the phosphorylation of Stat3 by PKC delta led to a negative regulation of Stat3 DNA binding and transcriptional activity. These results indicate that PKC delta is likely to be the kinase that phosphorylates Stat3 in response to IL-6 stimulation and suggest a possible regulatory role of PKC delta on Stat3 function.
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PMID:Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. 1044 19

The ability of ethanol to inhibit regenerative processes in the liver is thought to play a key role in the development of alcoholic liver disease. To understand the underlying mechanisms, we investigated the effects of ethanol on the Janus kinasesignal transducer and activator transcription factor (JAK-STAT) signaling pathways in hepatocytes. Treatment of freshly isolated adult rat hepatocytes with 10-100 mM ethanol rapidly (< 3 min) inhibits interleukin-6 (IL-6)-induced STAT3 activation, tyrosine and serine phosphorylation and IL-6-induced CCAAT enhancer binding protein (C/EBP) alpha and beta mRNA expression. Western analyses, in vitro kinase assays and in vivo cell labelling assays indicate that this inhibitory effect is not due to blocking the upstream-located JAK1, JAK2 or Tyk2 activation. On the contrary, acute ethanol exposure significantly potentiates IL-6-induced JAK1 autophosphorylation in vitro and in vivo. Pretreatment with sodium vanadate, a non-selective tyrosine phosphatase inhibitor, or with MG132 and lactacystin, proteasome inhibitors, does not abolish the ethanol inhibition of IL-6-induced STAT3 activation, suggesting that activation of protein tyrosine phosphatases or the ubiquitin-proteasome pathway is not involved. In view of the critical role of IL-6 signaling in liver regeneration, these findings suggest that the ability of biologically relevant concentrations of ethanol to markedly inhibit IL-6-induced STAT3 phosphorylation is one of the cellular mechanisms involved in the pathogenesis and progression of alcoholic liver diseases.
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PMID:Ethanol rapidly inhibits IL-6-activated STAT3 and C/EBP mRNA expression in freshly isolated rat hepatocytes. 1048 86

The bioactivity of interleukin-6 (IL-6) was found to be dramatically reduced in fluids from sites of inflammation. Here, we provide evidence that the neutrophil-derived serine proteases elastase, proteinase 3 and cathepsin G are mainly involved in its degradation and subsequent inactivation. The initially hydrolyzed peptide bonds were detected to be Val(11)-Ala(12) and Leu(19)-Thr(20) (elastase), Phe(78)-Asn(79) (cathepsin G) and Ala(145)-Ser(146) (proteinase 3). The soluble IL-6 receptor elicits a protective effect against the IL-6 inactivation by cathepsin G only. The inactivation of IL-6 by neutrophil-derived serine proteases might act as a feedback mechanism terminating the IL-6-induced activation of neutrophils.
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PMID:Evidence for a crucial role of neutrophil-derived serine proteases in the inactivation of interleukin-6 at sites of inflammation. 1056 3

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a well-known stimulus for the activation, differentiation and survival of monocytes (MO). Up to now most investigations focused on the short-term effects of GM-CSF. In this study we investigated the effects of GM-CSF on the long-term differentiation of human MO in the presence of serum. We found that MO-derived macrophages (Mphi) cultured with serum plus GM-CSF (GM-Mphi) were different from control Mphi (SER-Mphi) in terms of lipopolysaccharide (LPS)-stimulated cytokine release: GM-Mphi showed an increased tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production, especially at lower LPS concentrations, but the secretion of IL-10 was diminished. In addition, GM-Mphi secreted TNF-alpha but not IL-6 and IL-10, spontaneously. The spontaneous TNF-alpha production was not due to LPS contamination as it could not be blocked by anti-CD14 antibody. Flow cytometry revealed, however, that the receptor for LPS, CD14, was up-regulated on GM-Mphi and those Mphi released twice as much soluble CD14 into the supernatant as compared with SER-Mphi. The higher CD14 expression also resulted in an enhanced LPS-binding capacity of GM-Mphi. Furthermore, the LPS-response of GM-Mphi could only be blocked by about fourfold higher concentration of anti-CD14 antibody compared with SER-Mphi. In summary, GM-CSF promotes the generation of a pro-inflammatory type of Mphi in two different ways: first, the down-regulation of autocrine IL-10 production increases the release of cytokines such as IL-6 and TNF-alpha and second, the up-regulation of membrane and soluble CD14 expression leads to a higher sensitivity towards LPS-stimulation.
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PMID:Granulocyte-macrophage colony-stimulating factor modulates lipopolysaccharide (LPS)-binding and LPS-response of human macrophages: inverse regulation of tumour necrosis factor-alpha and interleukin-10. 1059 79

Mast cells (MC) are strategically located along blood vessels and, on activation, exocytose granules that contain many vasoactive mediators. Endothelial cell (EC) activation, which includes the production of such cytokines as interleukin-6 (IL-6) and IL-8, is a key event in vascular inflammation. In this study, the effects of purified MC granules (MCG) on the production of IL-6 and IL-8 by human coronary artery EC (HCAEC) were examined. HCAEC were cocultured with MCG in the presence or absence of lipopolysaccharide (LPS), and IL-6 and IL-8 levels in the culture medium were assayed by ELISA. Unactivated HCAEC produced only low levels of IL-6 or IL-8, and the addition of MCG alone resulted in little or no increase in production of these cytokines. LPS-activated HCAEC produced significant amounts of IL-6 and IL-8 in a dose-dependent and time-dependent fashion, which was amplified 2-3-fold by MCG at EC/MC ratios of 16:1-2:1. Scanning electron microscopy revealed direct communication between MCG and HCAEC. The enhancement of IL-6 and IL-8 production by MCG was abrogated when MCG were pretreated with the serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF). These results demonstrate that MCG interaction with HCAEC causes amplification of endotoxin-stimulated cytokine production via serine proteases present in MCG. The synergistic activation of EC by endotoxin and MCG proteases emphasizes the role of MC in amplifying vascular inflammation.
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PMID:Endotoxin and mast cell granule proteases synergistically activate human coronary artery endothelial cells to generate interleukin-6 and interleukin-8. 1080 70

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

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