The Experts below are selected from a list of 156 Experts worldwide ranked by ideXlab platform
Jürgen Bernhagen - One of the best experts on this subject based on the ideXlab platform.
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activation of the jnk signalling pathway by macrophage migration inhibitory factor mif and dependence on CXCr4 and cd74
Cellular Signalling, 2011Co-Authors: Hongqi Lue, Manfred Dewor, Lin Leng, Richard Bucala, Jürgen BernhagenAbstract:c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family and controls essential processes such as inflammation, cell differentiation, and apoptosis. JNK signalling is triggered by extracellular signals such as cytokines and environmental stresses. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine with Chemokine-like functions in leukocyte recruitment and atherosclerosis. MIF promotes MAPK signalling through ERK1/2, while it can either activate or inhibit JNK phosphorylation, depending on the cell type and underlying stimulation context. MIF activities are mediated by non-cognate interactions with the CXC Chemokine Receptors CXCR2 and CXCR4 or by ligation of CD74, which is the cell surface expressed form of the class II invariant chain. ERK1/2 signalling stimulated by MIF is dependent on CD74, but the receptor pathway involved in MIF activation of the JNK pathway is unknown. Here we comprehensively characterize the stimulatory effect of MIF on the canonical JNK/c-Jun/AP-1 pathway in fibroblasts and T cell lines and identify the upstream signalling components. Physiological concentrations of recombinant MIF triggered the phosphorylation of JNK and c-Jun and rapidly activated AP-1. In T cells, MIF-mediated activation of the JNK pathway led to upregulated gene expression of the inflammatory Chemokine CXCL8. Activation of JNK signalling by MIF involved the upstream kinases PI3K and SRC and was found to be dependent on CXCR4 and CD74. Together, these data show that the CXCR4/CD74/SRC/PI3K axis mediates a rapid and transient activation of the JNK pathway as triggered by the inflammatory cytokine MIF in T cells and fibroblasts.
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macrophage migration inhibitory factor in cardiovascular disease
Circulation, 2008Co-Authors: Alma Zernecke, Jürgen Bernhagen, Christian WeberAbstract:The highly conserved and archetypical yet atypical cytokine macrophage migration inhibitory factor (MIF) fulfills pleiotropic immune functions in many acute and chronic inflammatory diseases. Recent evidence has emerged from both expression and functional studies to implicate MIF in various aspects of cardiovascular disease. The present review is aimed at providing a synopsis of the involvement of MIF in the inflammatory pathogenesis of atherosclerosis and its consequences, namely unstable plaque formation, remodeling after arterial injury, aneurysm formation, myocardial infarction, or ischemia-reperfusion injury. In addition, other forms of myocardial dysfunction and inflammation and the role of MIF in angiogenesis are reviewed. The functional data are reconciled with recent progress in the identification of heptahelical (CXC Chemokine) Receptors for MIF, its prototypic role as their noncanonical ligand, and its signal transduction profile operative in atherogenic and inflammatory recruitment of mononuclear cells and in the oxidative damage and apoptosis of cardiomyocytes. Its unique features and functions clearly distinguish MIF from other cytokines implicated in atherogenesis and make it a prime target for achieving therapeutic regression of atherosclerosis. The potential of targeting or exploiting MIF for therapeutic strategies or as a diagnostic marker in the management of cardiovascular diseases or disorders is scrutinized.
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mif is a noncognate ligand of CXC Chemokine Receptors in inflammatory and atherogenic cell recruitment
Nature Medicine, 2007Co-Authors: Jürgen Bernhagen, Regina Krohn, Julia L Gregory, Rory R Koenen, Manfred Dewor, Ivan T Georgiev, Lin Leng, Alma Zernecke, Andreas Schober, Teake KooistraAbstract:The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the Chemokine Receptors CXCR2 and CXCR4 as functional Receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes CXCr2). Blockade of Mif but not of canonical ligands of CXCr2 or CXCr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays Chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition. © 2007 Nature Publishing Group.
Francoise Bachelerie - One of the best experts on this subject based on the ideXlab platform.
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the Chemokine sdf 1 CXCl12 binds to and signals through the orphan receptor rdc1 in t lymphocytes
Journal of Biological Chemistry, 2005Co-Authors: Karl Balabanian, Bernard Lagane, Simona Infantino, Ken Y C Chow, Julie Harriague, Barbara Moepps, Fernando Arenzanaseisdedos, Marcus Thelen, Francoise BachelerieAbstract:Combined phylogenetic and chromosomal location studies suggest that the orphan receptor RDC1 is related to CXC Chemokine Receptors. RDC1 provides a co-receptor function for a restricted number of human immunodeficiency virus (HIV) isolates, in particular for the CXCR4-using HIV-2 ROD strain. Here we show that CXCL12, the only known natural ligand for CXCR4, binds to and signals through RDC1. We demonstrate that RDC1 is expressed in T lymphocytes and that CXCL12-promoted chemotaxis is inhibited by an anti-RDC1 monoclonal antibody. Concomitant blockade of RDC1 and CXCR4 produced additive inhibitory effects in CXCL12-induced T cell migration. Furthermore, we provide evidence that interaction of CXCL12 with RDC1 is specific, saturable, and of high affinity (apparent KD approximately 0.4 nM). In CXCR4-negative cells expressing RDC1, CXCL12 promotes internalization of the receptor and chemotactic signals through RDC1. Collectively, our data indicate that RDC1, which we propose to rename as CXCR7, is a receptor for CXCL12.
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the Chemokine sdf 1 CXCl12 binds to and signals through the orphan receptor rdc1 in t lymphocytes
Journal of Biological Chemistry, 2005Co-Authors: Karl Balabanian, Bernard Lagane, Simona Infantino, Ken Y C Chow, Julie Harriague, Barbara Moepps, Fernando Arenzanaseisdedos, Marcus Thelen, Francoise BachelerieAbstract:Abstract Combined phylogenetic and chromosomal location studies suggest that the orphan receptor RDC1 is related to CXC Chemokine Receptors. RDC1 provides a co-receptor function for a restricted number of human immunodeficiency virus (HIV) isolates, in particular for the CXCR4-using HIV-2 ROD strain. Here we show that CXCL12, the only known natural ligand for CXCR4, binds to and signals through RDC1. We demonstrate that RDC1 is expressed in T lymphocytes and that CXCL12-promoted chemotaxis is inhibited by an anti-RDC1 monoclonal antibody. Concomitant blockade of RDC1 and CXCR4 produced additive inhibitory effects in CXCL12-induced T cell migration. Furthermore, we provide evidence that interaction of CXCL12 with RDC1 is specific, saturable, and of high affinity (apparent KD ≈ 0.4 nm). In CXCR4-negative cells expressing RDC1, CXCL12 promotes internalization of the receptor and chemotactic signals through RDC1. Collectively, our data indicate that RDC1, which we propose to rename as CXCR7, is a receptor for CXCL12.
Christian Weber - One of the best experts on this subject based on the ideXlab platform.
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macrophage migration inhibitory factor in cardiovascular disease
Circulation, 2008Co-Authors: Alma Zernecke, Jürgen Bernhagen, Christian WeberAbstract:The highly conserved and archetypical yet atypical cytokine macrophage migration inhibitory factor (MIF) fulfills pleiotropic immune functions in many acute and chronic inflammatory diseases. Recent evidence has emerged from both expression and functional studies to implicate MIF in various aspects of cardiovascular disease. The present review is aimed at providing a synopsis of the involvement of MIF in the inflammatory pathogenesis of atherosclerosis and its consequences, namely unstable plaque formation, remodeling after arterial injury, aneurysm formation, myocardial infarction, or ischemia-reperfusion injury. In addition, other forms of myocardial dysfunction and inflammation and the role of MIF in angiogenesis are reviewed. The functional data are reconciled with recent progress in the identification of heptahelical (CXC Chemokine) Receptors for MIF, its prototypic role as their noncanonical ligand, and its signal transduction profile operative in atherogenic and inflammatory recruitment of mononuclear cells and in the oxidative damage and apoptosis of cardiomyocytes. Its unique features and functions clearly distinguish MIF from other cytokines implicated in atherogenesis and make it a prime target for achieving therapeutic regression of atherosclerosis. The potential of targeting or exploiting MIF for therapeutic strategies or as a diagnostic marker in the management of cardiovascular diseases or disorders is scrutinized.
Karl Balabanian - One of the best experts on this subject based on the ideXlab platform.
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the Chemokine sdf 1 CXCl12 binds to and signals through the orphan receptor rdc1 in t lymphocytes
Journal of Biological Chemistry, 2005Co-Authors: Karl Balabanian, Bernard Lagane, Simona Infantino, Ken Y C Chow, Julie Harriague, Barbara Moepps, Fernando Arenzanaseisdedos, Marcus Thelen, Francoise BachelerieAbstract:Combined phylogenetic and chromosomal location studies suggest that the orphan receptor RDC1 is related to CXC Chemokine Receptors. RDC1 provides a co-receptor function for a restricted number of human immunodeficiency virus (HIV) isolates, in particular for the CXCR4-using HIV-2 ROD strain. Here we show that CXCL12, the only known natural ligand for CXCR4, binds to and signals through RDC1. We demonstrate that RDC1 is expressed in T lymphocytes and that CXCL12-promoted chemotaxis is inhibited by an anti-RDC1 monoclonal antibody. Concomitant blockade of RDC1 and CXCR4 produced additive inhibitory effects in CXCL12-induced T cell migration. Furthermore, we provide evidence that interaction of CXCL12 with RDC1 is specific, saturable, and of high affinity (apparent KD approximately 0.4 nM). In CXCR4-negative cells expressing RDC1, CXCL12 promotes internalization of the receptor and chemotactic signals through RDC1. Collectively, our data indicate that RDC1, which we propose to rename as CXCR7, is a receptor for CXCL12.
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the Chemokine sdf 1 CXCl12 binds to and signals through the orphan receptor rdc1 in t lymphocytes
Journal of Biological Chemistry, 2005Co-Authors: Karl Balabanian, Bernard Lagane, Simona Infantino, Ken Y C Chow, Julie Harriague, Barbara Moepps, Fernando Arenzanaseisdedos, Marcus Thelen, Francoise BachelerieAbstract:Abstract Combined phylogenetic and chromosomal location studies suggest that the orphan receptor RDC1 is related to CXC Chemokine Receptors. RDC1 provides a co-receptor function for a restricted number of human immunodeficiency virus (HIV) isolates, in particular for the CXCR4-using HIV-2 ROD strain. Here we show that CXCL12, the only known natural ligand for CXCR4, binds to and signals through RDC1. We demonstrate that RDC1 is expressed in T lymphocytes and that CXCL12-promoted chemotaxis is inhibited by an anti-RDC1 monoclonal antibody. Concomitant blockade of RDC1 and CXCR4 produced additive inhibitory effects in CXCL12-induced T cell migration. Furthermore, we provide evidence that interaction of CXCL12 with RDC1 is specific, saturable, and of high affinity (apparent KD ≈ 0.4 nm). In CXCR4-negative cells expressing RDC1, CXCL12 promotes internalization of the receptor and chemotactic signals through RDC1. Collectively, our data indicate that RDC1, which we propose to rename as CXCR7, is a receptor for CXCL12.
Alma Zernecke - One of the best experts on this subject based on the ideXlab platform.
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macrophage migration inhibitory factor in cardiovascular disease
Circulation, 2008Co-Authors: Alma Zernecke, Jürgen Bernhagen, Christian WeberAbstract:The highly conserved and archetypical yet atypical cytokine macrophage migration inhibitory factor (MIF) fulfills pleiotropic immune functions in many acute and chronic inflammatory diseases. Recent evidence has emerged from both expression and functional studies to implicate MIF in various aspects of cardiovascular disease. The present review is aimed at providing a synopsis of the involvement of MIF in the inflammatory pathogenesis of atherosclerosis and its consequences, namely unstable plaque formation, remodeling after arterial injury, aneurysm formation, myocardial infarction, or ischemia-reperfusion injury. In addition, other forms of myocardial dysfunction and inflammation and the role of MIF in angiogenesis are reviewed. The functional data are reconciled with recent progress in the identification of heptahelical (CXC Chemokine) Receptors for MIF, its prototypic role as their noncanonical ligand, and its signal transduction profile operative in atherogenic and inflammatory recruitment of mononuclear cells and in the oxidative damage and apoptosis of cardiomyocytes. Its unique features and functions clearly distinguish MIF from other cytokines implicated in atherogenesis and make it a prime target for achieving therapeutic regression of atherosclerosis. The potential of targeting or exploiting MIF for therapeutic strategies or as a diagnostic marker in the management of cardiovascular diseases or disorders is scrutinized.
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mif is a noncognate ligand of CXC Chemokine Receptors in inflammatory and atherogenic cell recruitment
Nature Medicine, 2007Co-Authors: Jürgen Bernhagen, Regina Krohn, Julia L Gregory, Rory R Koenen, Manfred Dewor, Ivan T Georgiev, Lin Leng, Alma Zernecke, Andreas Schober, Teake KooistraAbstract:The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the Chemokine Receptors CXCR2 and CXCR4 as functional Receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes CXCr2). Blockade of Mif but not of canonical ligands of CXCr2 or CXCr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays Chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition. © 2007 Nature Publishing Group.
