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  • NF-KAPPA-B  (6)
  • 1
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; PROTECTION ; CELL ; Germany ; MODEL ; MODELS ; NF-KAPPA-B ; ACTIVATION ; CELL ACTIVATION ; MECHANISM ; TRANSCRIPTION FACTOR ; mechanisms ; DELETION ; STEPS ; SIGNALING PATHWAYS ; PRODUCT ; SUPERFAMILY ; innate immunity ; Jun ; SOLUBLE RECEPTOR ; immune response ; IMMUNE-RESPONSE ; RECEPTORS ; INITIATION ; inflammation ; ANIMAL-MODELS ; immunoglobulin ; PRODUCTS ; LEADS ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; pattern recognition ; CLASS-III REGION ; DIABETIC VASCULOPATHY ; INFLAMMATORY RESPONSES
    Abstract: While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation
    Type of Publication: Journal article published
    PubMed ID: 15173891
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  • 2
    Keywords: HEPATOCELLULAR-CARCINOMA ; NF-KAPPA-B ; STEM-CELLS ; PROGENITOR CELLS ; REPERFUSION INJURY ; END-PRODUCTS RAGE ; ETHIONINE-SUPPLEMENTED DIET ; GROUP BOX 1 ; ISCHEMIA-REPERFUSION ; CHOLINE-DEFICIENT
    Abstract: The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor and member of the immunoglobulin superfamily. RAGE is mainly involved in tissue damage and chronic inflammatory disorders, sustaining the inflammatory response upon engagement with damage-associated molecular pattern molecules (DAMPs) such as S100 proteins and high-mobility group box 1 (HMGB1). Enhanced expression of RAGE and its ligands has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms. Here we show that RAGE supports hepatocellular carcinoma (HCC) formation in the Mdr2(-/-) mouse model, a prototype model of inflammation-driven HCC formation, which mimics the human pathology. Mdr2(-/-) Rage(-/-) (dKO) mice developed smaller and fewer HCCs than Mdr2(-/-) mice. Interestingly, although in preneoplastic Mdr2(-/-) livers RAGE ablation did not affect the onset of inflammation, premalignant dKO livers showed reduced liver damage and fibrosis, in association with decreased oval cell activation. Oval cells expressed high RAGE levels and displayed reduced proliferation upon RAGE silencing. Moreover, stimulation of oval cells with HMGB1 promoted an ERK1/2-Cyclin D1-dependent oval cell proliferation in vitro. Finally, genetic and pharmacologic blockade of RAGE signaling impaired oval cell activation in an independent mouse model of oval cell activation, the choline deficient ethionine-supplemented dietary regime. Conclusion: Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 23504974
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  • 3
    Keywords: NF-KAPPA-B ; IMMUNE-RESPONSES ; GLYCATION END-PRODUCTS ; CENTRAL-NERVOUS-SYSTEM ; CELL-ADHESION MOLECULE ; TOLL-LIKE RECEPTORS ; RHEUMATOID-ARTHRITIS ; SUSTAINED INTESTINAL INFLAMMATION ; NITRIC-OXIDE PRODUCTION ; PATTERN MOLECULES
    Abstract: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p 〈 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-kappaB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-kappaB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p 〈 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
    Type of Publication: Journal article published
    PubMed ID: 23729438
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; INHIBITION ; GENE ; GENE-EXPRESSION ; MICE ; TIME ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; TRANSCRIPTION FACTOR ; INDUCTION ; gene expression ; FIBER ; PRODUCT ; LIGANDS ; SUPERFAMILY ; GLYCATION END-PRODUCTS ; PROGRAMMED CELL-DEATH ; ALPHA-LIPOIC ACID ; microenvironment ; PAIN ; EPSILON-CARBOXYMETHYLLYSINE ; immunoglobulin ; NEUROPATHY ; OXIDATIVE-STRESS ; PERIPHERAL-NERVE ; PRODUCTS
    Abstract: Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches
    Type of Publication: Journal article published
    PubMed ID: 15599399
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  • 5
    Keywords: RECEPTOR ; INHIBITOR ; INVASION ; SURVIVAL ; tumor ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; PATHWAY ; VIVO ; MICE ; TIME ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; animals ; mechanisms ; BINDING ; cytokines ; STIMULATION ; NO ; CARE ; DESIGN ; DIFFERENCE ; NECROSIS-FACTOR-ALPHA ; BETA ; FACTOR-KAPPA-B ; LETHALITY ; INHIBITORS ; FACTOR-ALPHA ; CYTOKINE ; PANCREATITIS ; INTERLEUKIN-1 ; NUCLEAR ; USA ; prospective ; animal ; NICOTINE ; MEDICINE ; response ; INTERVENTIONS ; LIGATION ; cecal ligation and puncture ; cholinergic anti-inflammatory pathway ; CHOLINERGIC ANTIINFLAMMATORY PATHWAY ; MURINE ENDOTOXEMIA ; neostigmine ; neutrophil ; physostigmine ; SEPTIC SHOCK ; SYSTEMIC INFLAMMATORY RESPONSE ; VAGUS NERVE
    Abstract: Objective: Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo. Design: Prospective, randomized laboratory investigation that used an established murine sepsis model. Setting: Research laboratory in a university hospital. Subjects: Female C57BL/6 mice. Interventions: Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 mu g/kg), physostigmine (80 mu g/kg), neostigmine (80 mu g/kg), or solvent three times daily for 3 days. Measurements and Main Results: Treatment with physostigmine significantly reduced lethality (p 〈= .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p 〈= .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappa B (p 〈= .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha., interleukin-1 beta, and interleukin-6 (p 〈= .001), and pulmonary neutrophil invasion (p 〈= .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals. Conclusions: Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use
    Type of Publication: Journal article published
    PubMed ID: 18091537
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  • 6
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; VOLUME ; DEATH ; transcription ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDUCTION ; CONTRAST ; DENDRITIC CELLS ; LYMPH-NODES ; SIGNAL ; FORM ; DIFFERENCE ; CELL-DEATH ; SIGNALING PATHWAYS ; MIGRATION ; ONCOGENE ; ATHEROSCLEROSIS ; immune response ; IMMUNE-RESPONSE ; PERIPHERAL-BLOOD ; CD4(+) T-CELLS ; F ; AUTOIMMUNITY ; CYTOKINE ; PERSISTENT ; NODES ; RE ; STRENGTH ; CD40 LIGAND ; CD40-CD40 LIGAND ; IL-12 PRODUCTION ; PHYSIOLOGICAL STIMULI
    Abstract: Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c(+) peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals. (C) 2004 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 15113760
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