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Attilio Maseri - One of the best experts on this subject based on the ideXlab platform.

  • the 174g c Interleukin 6 polymorphism influences postoperative Interleukin 6 levels and postoperative atrial fibrillation is atrial fibrillation an inflammatory complication
    Circulation, 2003
    Co-Authors: Mario Gaudino, Felicita Andreotti, Roberto Zamparelli, Augusto Di Castelnuovo, Giuseppe Nasso, Francesco Burzotta, Licia Iacoviello, Maria Benedetta Donati, R Schiavello, Attilio Maseri
    Abstract:

    BACKGROUND: It has been suggested that inflammation can have a role in the development of atrial arrhythmias after cardiac surgery and that a genetic predisposition to develop postoperative complications exists. This study was conceived to verify if a potential genetic modulator of the systemic inflammatory reaction to cardiopulmonary bypass (the -174 G/C polymorphism of the promoter of the Interleukin-6 gene) has a role in the pathogenesis of postoperative atrial fibrillation (AF). Patients and Results- In 110 primary isolated coronary artery bypass patients the -174G/C Interleukin-6 promoter gene variant was determined. Interleukin-6, fibrinogen and C-reactive protein plasma levels were determined preoperatively, 24, 48, and 72 hours after surgery and at discharge. Heart rate and rhythm were continuously monitored for the first 36 to 48 hours; daily 12-lead electrocardiograms were performed thereafter until discharge. GG, CT, and CC genotypes were found in 62, 38, and 10 patients, respectively. Multivariate analysis (which included genotype, age, sex, and classical risk factors for AF) identified the GG genotype as the only independent predictor of postoperative AF. The latter occurred in 33.9% of GG versus 10.4% of non-GG patients (hazard ratio 3.25, 95%CI 1.23 to 8.62). AF patients had higher blood levels of Interleukin-6 and fibrinogen after surgery (P<0.001 for difference between the area under the curve). CONCLUSIONS: The -174G/C Interleukin-6 promoter gene variant appears to modulate the inflammatory response to surgery and to influence the development of postoperative AF. These data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication.

  • elevated levels of Interleukin 6 in unstable angina
    Circulation, 1996
    Co-Authors: Luigi M Biasucci, Alessandra Vitelli, Giovanna Liuzzo, Sergio Altamura, Giuseppina Caligiuri, Claudia Monaco, Antonio Giuseppe Rebuzzi, Gennaro Ciliberto, Attilio Maseri
    Abstract:

    Background Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of Interleukin-6, which is the major determinant of acute-phase–protein production by the liver. However, in unstable angina, there is no direct proof of the role played by Interleukin-6. Methods and Results We measured levels of Interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie, <3 pg/mL, in healthy volunteers) was detectable in 23 (61%) of 38 patients with unstable angina but in only 6 (21%) of 29 with stable angina (P<.01). Median Interleukin-6 levels were 5.25 pg/m...

  • Elevated Levels of Interleukin-6 in Unstable Angina
    Circulation, 1996
    Co-Authors: Luigi M Biasucci, Alessandra Vitelli, Giovanna Liuzzo, Sergio Altamura, Giuseppina Caligiuri, Claudia Monaco, Antonio Giuseppe Rebuzzi, Gennaro Ciliberto, Attilio Maseri
    Abstract:

    Background Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of Interleukin-6, which is the major determinant of acute-phase–protein production by the liver. However, in unstable angina, there is no direct proof of the role played by Interleukin-6. Methods and Results We measured levels of Interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie,

Stefan Rose-john - One of the best experts on this subject based on the ideXlab platform.

  • The soluble Interleukin-6 receptor and related proteins
    Best Practice & Research Clinical Endocrinology & Metabolism, 2015
    Co-Authors: Stefan Rose-john
    Abstract:

    Interleukin-6 is a cytokine involved in the regulation of the immune system and the central nervous system. Interleukin-6 binds to an Interleukin-6 receptor, and then associates with a dimer of the ubiquitously expressed gp130 receptor subunit, which initiates intracellular signaling. The Interleukin-6 receptor is found in a soluble form, which is generated by proteolytic cleavage and also to a minor extent by translation from an alternatively spliced mRNA. The complex of Interleukin-6 bound to the Interleukin-6 receptor can stimulate cells, which only express gp130. Such cells are not responsive to Interleukin-6 alone. We have for the first time identified the molecular basis of pro-and anti-inflammatory properties of Interleukin-6 and we have defined the generation of the soluble IL-6R as a crucial point in the regulation between these two properties. Furthermore, we have deduced a therapeutic principle, which enables us to exclusively block the pro-inflammatory activities of this important cytokine.

  • The pro- and anti-inflammatory properties of the cytokine Interleukin-6
    Biochimica et Biophysica Acta - Molecular Cell Research, 2011
    Co-Authors: Jürgen Scheller, Dirk Schmidt-arras, Athena Chalaris, Stefan Rose-john
    Abstract:

    Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, Interleukin-6 stimulates target cells via a membrane bound Interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound Interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to Interleukin-6 alone, they can respond to a complex of Interleukin-6 bound to a naturally occurring soluble form of the Interleukin-6 receptor. Therefore, the generation of soluble form of the Interleukin-6 receptor dramatically enlarges the spectrum of Interleukin-6 target cells. This process has been named trans-signaling. Here, we review the involvement of both signaling modes in the biology of Interleukin-6. It turns out that regenerative or anti-inflammatory activities of Interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of Interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of Interleukin-6 by the neutralizing anti-Interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. © 2011 Elsevier B.V.

  • Direct Determination of the Interleukin-6 Binding Epitope of the Interleukin-6 Receptor by NMR Spectroscopy
    Journal of Biological Chemistry, 2003
    Co-Authors: Andreas Schwantner, Stefan Rose-john, Andrew J. Dingley, Suat Özbek, Joachim Grötzinger
    Abstract:

    Abstract All cytokines belonging to the Interleukin-6 (IL-6)-type family of cytokines utilize receptors that have a modular build of several immunoglobulin-like and fibronectin type III-like domains. Characteristic of these receptors is a cytokine receptor homology region consisting of two such fibronectin domains defined by a set of four conserved cysteines and a tryptophan-serine-X-tryptophan-serine sequence motif. On target cells, Interleukin-6 first binds to its specific receptor and subsequently to a homodimer of the signal transducer protein gp130. The Interleukin-6 receptor consists of three extracellular domains. The N-terminal immunoglobulin-like domain is not involved in ligand binding, whereas the third membrane proximal fibronectin-like domain accounts for more than 90% of the binding energy to IL-6. Here, the key residues of this fibronectin-like domain involved in the interaction with IL-6 are described. Chemical shift mapping data with 15N-labeled IL-6R-D3 and unlabeled IL-6 coupled with recent structural data clearly reveal the epitope within the IL-6R-D3 responsible for mediating the high affinity interaction with its cognate cytokine.

  • Effect of soluble Interleukin-6 receptor on Interleukin-6 synthesis in human skin fibroblasts.
    Biochemical and Biophysical Research Communications, 1996
    Co-Authors: Joanna Cichy, Stefan Rose-john, Juliusz Pryjma, James Travis
    Abstract:

    Abstract In this study the ability of soluble Interleukin-6 receptor (sIL-6R) to stimulate Interleukin-6 (IL-6) synthesis in human fibroblasts is described. It was found that sIL-6R, in combination with endogenous or exogenous IL-6, markedly upregulated IL-6 synthesis. These data suggest that increased IL-6 production after stimulation by either Interleukin-1 or tumor necrosis factor-α would result in complex formation with sIL-6R, rapid uptake, and further synthesis of this cytokine. Furthermore, it would explain the decrease in sIL-6R plasma levels observed in patients suffering from sepsis.

Luigi M Biasucci - One of the best experts on this subject based on the ideXlab platform.

  • elevated levels of Interleukin 6 in unstable angina
    Circulation, 1996
    Co-Authors: Luigi M Biasucci, Alessandra Vitelli, Giovanna Liuzzo, Sergio Altamura, Giuseppina Caligiuri, Claudia Monaco, Antonio Giuseppe Rebuzzi, Gennaro Ciliberto, Attilio Maseri
    Abstract:

    Background Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of Interleukin-6, which is the major determinant of acute-phase–protein production by the liver. However, in unstable angina, there is no direct proof of the role played by Interleukin-6. Methods and Results We measured levels of Interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie, <3 pg/mL, in healthy volunteers) was detectable in 23 (61%) of 38 patients with unstable angina but in only 6 (21%) of 29 with stable angina (P<.01). Median Interleukin-6 levels were 5.25 pg/m...

  • Elevated Levels of Interleukin-6 in Unstable Angina
    Circulation, 1996
    Co-Authors: Luigi M Biasucci, Alessandra Vitelli, Giovanna Liuzzo, Sergio Altamura, Giuseppina Caligiuri, Claudia Monaco, Antonio Giuseppe Rebuzzi, Gennaro Ciliberto, Attilio Maseri
    Abstract:

    Background Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of Interleukin-6, which is the major determinant of acute-phase–protein production by the liver. However, in unstable angina, there is no direct proof of the role played by Interleukin-6. Methods and Results We measured levels of Interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie,

Stefan Rosejohn - One of the best experts on this subject based on the ideXlab platform.

  • the pro and anti inflammatory properties of the cytokine Interleukin 6
    Biochimica et Biophysica Acta, 2011
    Co-Authors: Jürgen Scheller, Athena Chalaris, Dirk Schmidtarras, Stefan Rosejohn
    Abstract:

    Abstract Interleukin-6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling , Interleukin-6 stimulates target cells via a membrane bound Interleukin-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130. Gp130 dimerizes, leading to the activation of Janus kinases and subsequent phosphorylation of tyrosine residues within the cytoplasmic portion of gp130. This leads to the engagement of phosphatase Src homology domains containing tyrosin phosphatase-2 (SHP-2) and activation of the ras/raf/Mitogen-activated protein (MAP) kinase (MAPK) pathway. In addition, signal transducer and activator of transcription factors are recruited, which are phosphorylated, and consequently dimerize whereupon they translocate into the nucleus and activate target genes. Interestingly, only few cells express membrane bound Interleukin-6 receptor whereas all cells display gp130 on the cell surface. While cells, which only express gp130, are not responsive to Interleukin-6 alone, they can respond to a complex of Interleukin-6 bound to a naturally occurring soluble form of the Interleukin-6 receptor. Therefore, the generation of soluble form of the Interleukin-6 receptor dramatically enlarges the spectrum of Interleukin-6 target cells. This process has been named trans-signaling . Here, we review the involvement of both signaling modes in the biology of Interleukin-6. It turns out that regenerative or anti-inflammatory activities of Interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of Interleukin-6 are rather mediated by trans-signaling . This is important since therapeutic blockade of Interleukin-6 by the neutralizing anti-Interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases.

  • Interleukin 6 and soluble Interleukin 6 receptor direct stimulation of gp130 and hematopoiesis
    Blood, 1998
    Co-Authors: Malte Peters, Albrecht M Muller, Stefan Rosejohn
    Abstract:

    T HE Interleukin-6 (IL-6) family of cytokines acts via receptor complexes that contain at least one subunit of the signal transducing protein gp130.[1][1] The family comprises IL-6, IL-11, ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF), and oncostatin M

Kelly R. Miller - One of the best experts on this subject based on the ideXlab platform.

  • Essential role of Interleukin-6 in post-stroke angiogenesis.
    Brain, 2012
    Co-Authors: Karen Gertz, Golo Kronenberg, Roland E. Kälin, Tina Baldinger, Christian Werner, Mustafa Balkaya, Julian Hellmann-regen, Jan Kröber, Kelly R. Miller
    Abstract:

    Ambivalent effects of Interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of Interleukin-6 after stroke have not been investigated. Here, we subjected Interleukin-6 knockout (IL-6−/−) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6−/− mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6−/− mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6−/− mice. In addition, systemic neoangiogenesis was impaired in IL-6−/− mice. Transplantation of Interleukin-6 competent bone marrow into IL-6−/− mice (IL-6chi) did not rescue Interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6chi mice recapitulated the major effects of Interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of Interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with Interleukin 6-induced robust Interleukin-6 messenger RNA transcription in each case, whereas oxygen–glucose deprivation did not. However, oxygen–glucose deprivation of organotypic brain slices resulted in strong upregulation of Interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, Interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection. * Abbreviations : BrdU  :  5-bromo-2-deoxyuridine GFP  :  green florescent protein gp130  :  glycoprotein 130 IL-6  :  Interleukin 6 MCAO  :  middle cerebral artery occlusion STAT  :  signal transducer and activator of transcription VEGF  :  vascular endothelial growth factor

  • Essential role of Interleukin-6 in post-stroke angiogenesis.
    Brain : a journal of neurology, 2012
    Co-Authors: Karen Gertz, Golo Kronenberg, Roland E. Kälin, Tina Baldinger, Christian Werner, Mustafa Balkaya, Julian Hellmann-regen, Jan Kröber, Kelly R. Miller
    Abstract:

    Ambivalent effects of Interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of Interleukin-6 after stroke have not been investigated. Here, we subjected Interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of Interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue Interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of Interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of Interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with Interleukin 6-induced robust Interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of Interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, Interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.